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Sexual addiction 25 years on: A systematic and methodological review of empirical literature and an agenda for future research

Affiliations.

1 Department of Psychology, Bowling Green State University, Bowling Green, OH, USA. Electronic address: [email protected].
2 Department of Psychology, Bowling Green State University, Bowling Green, OH, USA.
3 Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
4 Department of Psychology, University of Nevada, Las Vegas, Las Vegas, NV, USA.
PMID: 33038740
DOI: 10.1016/j.cpr.2020.101925

In 1998, Gold and Heffner authored a landmark review in Clinical Psychology Review on the topic of sexual addiction that concluded that sexual addiction, though increasingly popular in mental health settings, was largely based on speculation, with virtually no empirical basis. In the more than two decades since that review, empirical research around compulsive sexual behaviors (which subsumes prior research about sexual addiction) has flourished, ultimately culminating in the inclusion of a novel diagnosis of Compulsive Sexual Behavior Disorder in the eleventh edition of the World Health Organization's International Classification of Diseases. The present work details a systematic review of empirical research published between January 1st, 1995 and August 1st, 2020 related to compulsive sexual behaviors, with a specific focus on evaluating the methodologies of that literature. This review yielded 371 papers detailing 415 individual studies. In general, the present review finds that, although research related to compulsive sexual behaviors has proliferated, much of this work is characterized by simplistic methodological designs, a lack of theoretical integration, and an absence of quality measurement. Moreover, the present review finds a virtual absence of high-quality treatment-related research published within this time frame. Implications of these findings for both clinical practice and future research are discussed.

Keywords: Behavioral addiction; Compulsive sexual behavior disorder; Hypersexuality; Pornography addiction; Sexual addiction.

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Debating the Conceptualization of Sex as an Addictive Disorder

Sex and Addiction (R Reid, Section Editor)
Published: 05 July 2015
Volume 2 , pages 195–201, ( 2015 )

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Drew A. Kingston 1 , 2

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Three predominant pathophysiological models have been applied to hypersexuality, which were developed based on observed similarities with obsessive-compulsive disorders, impulse-control disorders, and addictions. Each model was intended to elucidate etiological mechanisms and symptom profile, and facilitate effective treatment. Unfortunately, there are a number of conceptual problems inherent in these models, and clinicians and researchers have typically adopted one descriptive model and have applied it to all individuals presenting with hypersexuality. In this paper, I review the utility and applicability of the sexual addiction conceptualization, arguably the most common model used in both academia and popular media in describing this behavior. Emphasis is placed on the similarities and differences between hypersexuality and addictions, including clinical characteristics, neurobiological underpinnings, diagnostic co-morbidity, and treatment response.

Sexual Addiction

Sex Addiction

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Introduction

Hypersexuality has been described for some time [ 1 – 3 ] although sexological research has predominantly focused on disorders characterized by low levels of sexual desire and response rather than high levels of sexual behavior. Hypersexuality is defined as a “stronger than usual urge to have sexual activity” ([ 4 ], p823, [ 2 , 3 ]) and is most often associated with the paraphilic disorders [ 5 ]. However, a number of researchers and clinicians have suggested that non-paraphilic hypersexuality can cluster with other relevant symptoms, such as loss of control over sexual behavior, the use of sex in response to dysphoric mood, and the continuation of the behavior despite adverse consequences, to represent a distinct psychopathological condition. Labels used in describing this putative construct include; Don Juanism, erotomania, nymphomania, paraphilia-related disorder, satyriasis, sexual compulsivity, sexual impulsivity, and most recently, hypersexual disorder. Footnote 1 Most of these terms are poorly defined and used interchangeably throughout the literature. In addition to such descriptive diversity, the field has been plagued by a number of other problems, such as a relative lack of empirical research as compared to clinical anecdote, inadequate sampling methods, as well as definitional and conceptual ambiguity [ 6 , 7 ].

Conceptual problems were noted decades ago [ 8 , 9 ], and there has been little progress made toward resolving such issues. In this paper, I review the evidence for an addiction-based conceptualization of hypersexual disorder, probably the most widely adopted conceptual model in use today, and I focus specifically on the similarities and differences between hypersexual disorder and addictions, including shared clinical characteristics, neurobiological processes, co-morbidity, and responsiveness to treatment.

Conceptual Models of Hypersexuality Disorder

Considerable attention has been directed toward how best to conceptualize hypersexual disorder. There are three predominant pathophysiological models, which have been developed based on observed similarities between hypersexual disorder and obsessive-compulsive disorders (sexual compulsivity), impulse-control disorders (sexual impulsivity), and addictions (sexual addiction). Each model encompasses similar features, such as impaired behavioral self-regulation and the criterion for clinical significance; however, there are key differences with respect to underlying motivational states. That is, the extent to which the underlying behavior is driven by features of impulsivity or compulsivity.

Although often used interchangeably, impulsivity and compulsivity are relatively distinct constructs. Impulsivity is typically defined as a “tendency to act spontaneously and without deliberation” ([ 10 ] p313) and as a predisposition toward rapid, unplanned reactions to either internal or external stimuli without regard for negative consequences [ 11 ]. More recently, impulsivity is seen as a complex cluster of lower-order traits, including sensation-seeking, lack of planning, lack of perseverance, and positive and negative urgency [ 12 ]. Theoretical approaches toward understanding impulsivity have focused on a strong approach motivation combined with a weak avoidance motivation and underlying problems in self-regulation [ 13 ]. Compulsivity is also a complex phenomenon but, in contrast to impulsivity, is characterized by repetitive actions that are intended to reduce anxiety or distress [ 4 ]. Individuals with compulsive traits are typically hypervigilant, and they exhibit a desire to avoid harm and reduce anxiety. These traits have been embedded within most definitions of addiction.

Defining Addiction

Addiction describes a maladaptive pattern of substance use with impaired control and adverse consequences. According to the American Society of Addiction Medicine [ 14 ], addiction is characterized as a chronic disease involving brain reward mechanisms and related circuitry, along with other associated factors, such as problems with behavioral self-control and craving. In DSM-5, addiction Footnote 2 is characterized by a cluster of cognitive, behavioral, and physiological symptoms related to the continued use of the substance despite adverse consequences ([ 4 ], p483). Twelve criteria defining addiction are listed in the DSM-5 ([ 4 ], p483-484), which are grouped into four categories: impaired control (including diminished ability to resist cravings), social impairment, risky use, and pharmacological criteria (i.e., tolerance and withdrawal).

In addition to important diagnostics features, addiction has also been delineated by distinct phases [ 15 ]. That is, initial consumption of the substance is primarily motivated by impulsivity and principles of positive reinforcement (i.e., hedonically rewarding properties of the drug) toward compulsive traits and principles of negative reinforcement, which are associated with relieving dysphoric mood associated with abstinence and/or from adverse environmental experiences. This transition has been supported in experimental research (e.g., [ 16 ]).

The contemporary formulation of addiction is generally restricted to the problematic use of psychoactive substances; however, there is a trend toward categorizing certain behaviors under a singular model of addiction, often referred to as behavioral addictions or process addictions [ 17 – 19 ]. Several behavioral addictions have been proposed, such as compulsive buying [ 20 ], exercise addiction [ 21 ], and excessive tanning [ 22 ], and each are seen as virtually synonymous with substance addictions with the exception that a particular behavior replaces the alcohol or drug of choice [ 23 ]. Currently, only Gambling Disorder (formerly termed Pathological Gambling) has received enough empirical support to be officially reclassified as a non-substance-related disorder [ 4 ]. Internet Gaming Disorder [ 24 ] was included in the appendix of DSM-5 among the conditions in which future research is encouraged.

It should be noted that categorizing behaviors under a singular model of addiction has been challenged given the tendency for expansive models to oversimplify complex phenomena and to obscure key differences between disorders [ 17 , 25 ]. Although broadening the concept of addiction promotes heuristic utility, some suggest decreased clinical utility, as it neglects to elucidate key mechanisms within particular disorders [ 26 ].

Defining Sexual Addiction

As with other behavioral addictions, sexual addiction is conceptualized as being synonymous with substance use disorders. The notion that sexual behavior could be potentially addictive was first introduced by Orford [ 9 ], but it has become most widely attributed to Patrick Carnes’ [ 27 ] book: Out of the Shadows: Understanding Sexual Addiction . Carnes described sexual addiction as representing a pathological relationship with a mood-altering experience ([ 27 ], p4), and he, along with others [ 28 , 29 ] have identified shared clinical characteristics between non-paraphilic (as well as paraphilic) hypersexuality and addiction.

Clinical Characteristics

Similar to substance-related disorders, sexual addiction has been characterized by intense, frequent preoccupation with sex, loss of control in regulating sexual behavior, and an inability to stop despite adverse consequences. A number of studies with relatively small clinical samples have shown that a significant proportion of self-identified sexual addicts report recurrent and intense sexual urges that are difficult to control and have led to some form of adverse consequences or personal distress [ 30 , 31 ]. Many of these reported characteristics are similar to those emphasized in standard definitions of addiction, such as the DSM [ 4 ]. Wines [ 32 ], for example, compared substance dependence criteria based on DSM-IV [ 33 ] with the self-reported symptoms of 53 self-identified sexual addicts attending 12-step programs for sexual addiction. Results demonstrated that each of the seven criteria listed in the DSM were endorsed by the majority of the clinical sample. More specifically, 87 % of the sample endorsed features associated with social impairment, 85 % experienced risky use, 94 % experienced impaired control, whereas 74 and 98 % experienced tolerance and withdrawal, respectively. The aforementioned studies investigating clinical characteristics, however, are limited due to the small sample sizes and are also likely influenced by an ascertainment bias, such that individuals experiencing such symptoms are likely to be present in selected treatment samples.

In addition to specific clinical characteristics, such as those reported in DSM-5, Koob [ 15 ] emphasized features of impulsivity and compulsivity. As noted earlier, addictive behavior has been characterized by the progression from impulsivity (i.e., using the substance for pleasure) to compulsivity (i.e., using the substance to escape from negative emotional states). The degree to which hypersexual patients exhibit compulsive versus impulsive traits have been specifically used to support the obsessive-compulsive [ 25 , 34 ] and impulse-control disorder models [ 35 , 36 ], respectively. However, the literature has failed to produce a consistent and unified phenomenological profile [ 7 ]. Indeed, it is clear that some individuals with hypersexuality exhibit compulsivity; that is, dysregulated sexuality to alleviate negative emotional states [ 30 , 37 ], whereas others have found that individuals show impulsivity directed toward enhancing positive emotional states [ 36 , 38 – 40 ]. In addition to comparisons across samples, such contradictions in motivational states have been indicated within samples. For example, Raymond et al. [ 37 ] indicated one third of participants in their sample found their thoughts to be intrusive and that 87 % attempted to resist such urges, which was evidence for compulsivity. However, mean scores on the impulsivity subscale of the Minnesota Personality Questionnaire [ 41 ] were indicative of higher levels of impulsivity when compared to normative samples.

In sum, these investigations suggest that both impulsive and compulsive traits can be evident in a sample of individuals presenting with hypersexual disorder. As such, an adequate conceptualization of hypersexual disorder must allow for the inclusion of impulsive and/or compulsive features. Interestingly, early descriptions of sexual addiction identified both compulsivity and impulsivity. Goodman [ 28 ], for example, stated that the function of excessive sexual behavior was both to produce pleasure and provide escape from pain, which highlighted the divergent motivations underlying such behavior. The progression from impulsivity to compulsivity, as described in some addiction models, may be evident among individuals exhibiting hypersexual disorder but research addressing this issue is needed. Alternatively, there is also the possibility that the progression is reversed; that is, individuals may engage in sexual behaviors to regulate negative mood and then, due to principles of reinforcement, engage in such activities to increase pleasure and positive mood states.

An integrated continuum including compulsive and impulsive features is not new nor is it specific to sexual addiction models; in fact, such a conceptualization has been described within the obsessive-compulsive spectrum disorders model (OCSDs; [ 42 , 43 ]). The OCSD incorporates several disorders, placed along a continuum, based on perceived similarities with obsessive-compulsive disorders, such as symptom profile, etiology, family history, and treatment response. The continuum includes pure compulsive behaviors (e.g., body dysmorphic disorder) at the one extreme end of the spectrum and pure impulsive behaviors (e.g., pathological gambling) at the other end [ 44 ]. Within the OCSD model, hypersexual disorder is generally regarded as a disorder at the impulsive end of the spectrum [ 43 ], which is consistent with some studies suggesting a predominantly sensation-seeking motivational mechanism driving such behavior (e.g., [ 40 , 45 ]) but is clearly inconsistent with other research (e.g., [ 25 ]). Additionally, several criticisms have been directed at the OCSD model, which have typically focused on whether the disorders have been adequately classified along the spectrum and the degree to which disorders share a similar treatment response [ 46 ].

However, despite the predominant focus of hypersexuality along the impulsive side of the spectrum, the OCSD model advances a useful concept in understanding the heterogeneous presentation of hypersexuality. That is, compulsivity and impulsivity may co-occur, either simultaneously or at different times, within a particular disorder [ 47 , 48 ]. This hypothesis has received some empirical support, both with regard to behavioral disorders in general (e.g., eating disorders) and with hypersexual disorder, in particular.

Neurological Similarities

Similarities between neurological substrates of addiction and non-substance-related behaviors have been identified to support behavioral manifestations of addiction [ 49 ]. The neurobiological mechanisms of addiction have been largely determined from animal models and predominantly relate to certain brain circuits, particularly within the mesolimbic reward pathway, and neurochemical changes (e.g., dopaminergic and serotonergic dysregulation) occurring in these areas of the brain. Among the various behavioral addictions, research has predominantly supported the neurological similarities between substance use disorders and gambling disorder (see [ 23 ] for a review).

Although neurological processes underlying human sexual behavior are still relatively unexplored, it is generally acknowledged that neurotransmitters, particularly dopamine and serotonin, play a role in sexually appetitive behavior and that sexual arousal affects the mesolimbic dopamine pathway [ 50 , 51 ]. In animal models, dopamine is one of the primary neurotransmitters involved in facilitating both the appetitive and consummatory phase of sexual functioning [ 52 ], and dopamine agonists have both facilitated and restored mounting behaviors, whereas dopamine antagonists decreased the number of mounts, intromissions, and ejaculations [ 53 , 54 ].

Mesolimbic dopamine functioning has not been systematically examined among individuals with and without hypersexuality or hypersexual disorder. Much of the evidence for dopamine’s role in hypersexuality has come from pharmacological interventions, and such research has been published in a number of case reports. There are several examples where increasing levels of dopamine in Parkinsonian patients have been associated with the emergence of both non-paraphilic and paraphilic hypersexuality (e.g., [ 55 ]) and that the reductions in dopamine levels have reduced hypersexual behavior [ 56 ].

Co-morbidity

The co-occurrence between hypersexual disorder and substance addictions has been posited as an important indicator of etiology and may be indicative that the disorders do not represent independent phenomena but rather, are different phenotypes of the same underlying disorder. Substance use disorders tend to be one of the most frequently co-occurring psychiatric disorders among individuals with hypersexual disorder [ 57 , 58 ], but there have only been a few studies with nationally representative samples that have assessed the co-morbidity between hypersexuality and substance addictions. For example, Ramrakha et al. [ 59 •] analyzed data collected on a nationally representative sample of 1037 men and women in New Zealand. Results indicated that the risk of substance dependence disorder increased with increasing numbers of sexual partners for both men and women. This study, however, did not directly assess hypersexual disorder, and the average number of sexual partners would not have met the behavioral criterion for this disorder. In a large, representative Swedish sample, Långström and Hanson [ 60 ] also found that hypersexuality was associated with heavy drinking and illicit drug use.

Several studies also report co-morbidity between hypersexual behavior and substance use disorders within clinically relevant samples. Carnes [ 61 ] surveyed 289 sexual addicts and found the majority of the participants experienced multiple addictions, and slightly less than half of the sample reported chemical dependency as their primary concurrent addiction. Black et al. [ 30 ] reported that the most common co-occurring disorder in the sample was a substance use disorder with 23 (64 %) of the sample experiencing both hypersexual disorder and a substance use disorder. Opitz, Tsytsarev, and Froh [ 62 ] reported substance abuse to be one of the significant factors associated with female hypersexual disorder, such that it accounted for 4 % of the variance of hypersexual disorder, next only to depression, which accounted for 28.5 % of the variance. In a larger clinical sample of 432 men and 193 women receiving services from a sexually transmitted infection clinic, Kalichman and Cain [ 58 ] found that higher scores on the sexual compulsivity scale [ 63 ] were strongly associated with greater use of substances within sexual contexts as well as higher scores on alcohol and drug abuse screening tests; the participants were also more likely to have abused cocaine and inhalants in the previous 3 months than individuals with lower scores on this measure. Most recently, Berberovic [ 57 ] found that substance abuse was also highly co-morbid with hypersexual disorder, as assessed using the sexual compulsivity scale, in a sample of students recruited from four large universities. Specifically, drug users were approximately 3.5 times more likely to be classified hypersexual than non-drug users. Significant correlations were also reported between hypersexuality and alcohol and cigarette addictions.

Data obtained from both representative and clinical samples suggest that the co-occurrence between substance addictions and hypersexual disorder is common and points to a common pathophysiology. However, it is not entirely clear whether alcohol or drug use simply disinhibits hypersexual behavior. Additionally, although substance use disorders are one of the more frequently co-occurring disorders with hypersexual disorder, there are a number of other co-morbid conditions. Other psychiatric disorders, such as mood and anxiety disorders [ 64 ], attention-deficit hyperactivity disorder [ 65 ], as well as impulse-control disorders and the disorders previously referred to under the personality disorder section of earlier DSM texts [ 30 ] have been identified.

Responsiveness to Treatment

Treatment protocols used with substance-based addictions have largely informed interventions provided to individuals with hypersexual disorder. Unfortunately, there have been few high-quality outcome studies demonstrating the efficacy of these approaches. The non-pharmacological treatments used for both disorders are based on relapse prevention and utilize cognitive-behavioral techniques. Despite the limited data, the use of relapse prevention is the current treatment of choice for both substance-based addictions and hypersexual disorder [ 66 ], with some studies showing some promising results (see [ 67 ] for a review).

In addition, 12-step programs, which were initially designed for substance-based addictions, have been adapted and used to treat hypersexual disorder. Several researchers have criticized the utility of the 12-step approach for both substance-based addictions and other addictions [ 7 , 68 ]. In particular, Coleman [ 25 ] and Keane [ 17 ] have suggested that problems identified within the 12-step treatment approach for hypersexual disorder are indicative of the inappropriate adaptation of the addiction model to hypersexual disorder. One of the significant concerns with the adapted 12-step approach for problematic hypersexuality is the notion of rejecting personal control. This perspective diametrically opposes empirically validated cognitive-behavioral treatment in general and specific models of rehabilitation, in particular, which emphasizes the notion of accepting the role of personal choice and responsibility and instituting greater insight into the role of cognitions and emotions in behavioral change.

In addition to psychological interventions, there are some pharmacological agents that are used in the treatment of substance addiction that have shown some promise in the treatment of hypersexual disorder, although well-designed experimentally controlled designs are lacking. Naltrexone, for example, is an opioid antagonist medication used for the treatment of alcohol use disorders and opioid addiction. Previous studies have supported its efficacy in the treatment of substance use disorders [ 69 ]. Raymond, Grant, Kim, and Coleman [ 70 ] reported on two cases reporting hypersexuality that were successfully treated with Naltrexone. Bostwick and Bucci [ 71 ] presented a case of a 24-year-old man requesting treatment for his sexual addiction. This individual reported a preoccupation with Internet pornography and was spending hours each day chatting online, masturbating, and meeting cyber contacts for spontaneous and unprotected sex. The patient was prescribed Sertraline as well as various types of psychosocial counseling with little improvement. After the addition of Naltrexone, the patient reported significant improvement in his ability to control his sexual behaviors. When the Naltrexone was discontinued, the cravings returned and when the medication was re-administered, the cravings again diminished.

Classification systems are intended to elucidate etiological mechanisms and symptom profile, and facilitate effective treatment. Unfortunately, several contradictory explanatory models have been used with hypersexual disorder, and clinicians and researchers have typically adopted one descriptive model and have applied it to all individuals presenting with this syndrome. Consequently, it is not surprising that there is a lack of consensus regarding definition and symptom presentation. In this paper, I reviewed the evidence for the addiction-based model of hypersexual disorder. A number of similarities between addictions and hypersexuality have been noted, including shared clinical characteristics, neurobiological profile, co-morbidity, and treatment response. However, in contrast to Gambling Disorder, research is insufficient to support the adoption and implementation of this model. The extant literature has shown substantial heterogeneity among individuals presenting with hypersexual disorder, both with respect to motivational drive states (i.e., impulsivity versus compulsivity) and in terms of symptom profile [ 72 •]. Such heterogeneity has obvious implications for treatment.

A number of researchers have suggested that theoretically neutral terms and models be used in describing hypersexual disorder [ 6 , 7 , 51 ]. The sexual desire disorders model (see Kafka, [ 73 ]) and dual control model ([ 74 ], also see [ 75 ] for a review) are useful models as they are not bound to current explanatory mechanisms and consequently permit a range of etiological factors associated with hypersexuality. Importantly, theoretically neutral conceptual models and terminology allow for considerable flexibility in assessing motivational drive states that are important for the design and implementation of treatment for hypersexual disorder.

I use the term hypersexual disorder throughout this review except when referring to specific conceptual models (e.g., sexual addiction). Hypersexual disorder was the term used by the DSM-5 Sexual Disorders Work Group (also see Kafka, 2010). Some have criticized this term predominantly because some clients can present with clinically relevant symptomatology but not be engaging in statistically excessive sexual behavior.

The DSM-5’s substance-related disorders workgroup selected the term substance use disorder as the official diagnostic label rather than addiction, as the latter term was seen as controversial, pejorative, and ambiguous. Nevertheless, the two terms are virtually synonymous.

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Kingston, D.A. Debating the Conceptualization of Sex as an Addictive Disorder. Curr Addict Rep 2 , 195–201 (2015). https://doi.org/10.1007/s40429-015-0059-6

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Socioaffect Neurosci Psychol

Sexual addiction: insights from psychoanalysis and functional neuroimaging

Vincent estellon.

1 Laboratoire de Psychologie Clinique et de Psychopathologie (LPCP, EA 4056) Institut de Psychologie, Université Paris Descartes, Boulogne-Billancourt, France

Harold Mouras

2 Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP, EA 4559), UFR de Médecine, Université de Picardie Jules Vernes, Amiens, France

Sexual motivation is a fundamental behavior in human. For a long time, this behavior has been somehow ignored from psychological and neuroscientific research. In this article – reflecting the collaboration of a clinical psychologist and a neuroscientist – we show that in the current period, sexual affiliation is one of the most promising affiliation context to articulate a debate, a dialog and convergence points between psychoanalysis and neuroscience. Recent data on healthy sexual behavior and its compulsive variant are discussed under the prism of neuroscience and psychoanalysis.

The modern western society in which we live is slowly but surely conditioning women and men – children or adults – to a world where whatever we desire must be available for immediate acquisition. With a profusion of an end to waiting and frustration ‘unlimited’ consumer products are on offer. In this context, one that would rather ignore the feelings of frustration associated with abstinence, sexual behavior has also known an evolution in which the laws of supply and demand have come to reign, along with the rules of free competition, giving to ‘sex’ objects the same status as any other product. In just a few decades, access to pornography has not only been developed but also became banal. We are far from the censure of the early 20th century when kissing scenes were simply cut from cinematographic reels. Consumer studies show that on Google , the world’s number one search motor, the terms ‘sex’, ‘love’, ‘porn’ arrive at the fore of all requests by both type and nature. Sexuality has become recreational, and even imperative. In effect, it was as if the slogan of the new societal Super-ego had become: ‘Unfettered and unlimited pleasure is a must!’

In these dynamics, in which the power of images is constantly growing, where screens (television, internet, telephone, etc.) have replaced books and notebooks, the challenge of actually having to elaborate a thought process is in no way facilitated. One can question the ever-more important role of pornography as a new educational tool of sexuality, its effects on the psychic apparatus in its capacity to imagine or fantasize the sexual. The danger being that external images come little by little to replace fantasies (produced from within). The subject, thus, passes from an active role (implied in fantasmatic production or in the imagination) to passivity, in the act of consuming images (magazines, films). Progressively, sexual excitement is increasingly distanced from the loving feelings associated with a relationship. The fact of loving implies both an encounter and sharing, loving someone else has the particular power of being able to tear a person away from a regressive position of narcissic omnipotence in which he believes himself to be self-sufficient, capable of everything, all alone . If ‘I can do everything all on my own’, I don’t need anyone else. Yet, when I am attracted by another, I recognize that I am lacking, and in a certain passive manner, in expectation of and dependent on another. Loving, thus, implies an acceptation – by the other – of something of one’s own deficiencies. And that other, come to that, can never fully satisfy these deficiencies … And yet, in the affective splitting of the sex-addict , not being completely satisfied is equal to not being satisfied at all. Here, there are no half-measure. As soon as there is any frustration, one must, therefore, do away with this ‘other’, to be replaced by a new one, and so on … If desire, which can be fantasized without necessarily being accomplished, is also born from the frustration associated with absence and a sense of missing, it would seem that this regresses to the quality of a need in addictive sexuality.

The concept of addictive sexuality

In the history of psychiatry, the terms of ‘hypersexuality’ (Jim Orford, 1985 ), of ‘satyriasis’, of ‘donjuanism’ in men, and of ‘nymphomania’ in women have been used. From the end of the 19th century, Ernst Kretschmer isolated the category of ‘frenetic masturbaters’. Recently, the terms of ‘compulsive sexuality’, ‘sexual intoxication’ (Claude Crépault, 1993 ), ‘atypical impulsion disorder’ (Barth & Kinder, 1987 ), ‘neo-sexualities’, and ‘addictive sexuality’ (Mac Dougall, 1978 ) have appeared. The dependency here is not a dependence on a toxic object but rather a behavioral dependency in which sexual activity, or the seeking of it, is experienced in an obsessive and compulsive fashion. As early as 1978, the British psychoanalyst Joyce Mac Dougall introduced the term of ‘addictive sexuality’ in her book ‘Plaidoyer pour une certaine anormalité’. She was designating subjects obsessed by sex, ‘slaves of quantity’. It was an American psychologist (Carnes, 1983 , 1989a , 1989b , 1991 , 2001 ) who specifically developed the concept of sexual dependency in his best-seller ‘Out of the Shadows’. On the medical level and in the scientific literature, the notion of sexual dependency was developed by Goodman ( 1990 , 1993 ), a psychiatrist of psychoanalytic orientation.

In the DSM-IV (DSM-IV, 1996 ) the classification manual of psychiatric disorders, addictive sexuality does not appear as such but is listed rather in the vague category of ‘unspecified sexual disorders’. The given definition also remains somewhat vague: ‘The disarray resulting from a mode of repetitive sexual relations implying a succession of sexual partners that the individual only perceives as objects to be used.’

In order to better detect subjects suffering from addictive sexuality, Patrick Carnes and Robert Weiss put together a questionnaire – The Sexual Addiction Screening Test – in two versions (one for the gay and bisexual population, another for the heterosexual population). If responses to the 25 questions result in 13 positive answers or more, the subject has a problem with addictive sexuality. The 1980s, marked by the appearance of the AIDS virus, were propitious to new research on addictive and compulsive sexual behavior (CSB) within which habitual promiscuity with multiple partners appears as an important risk factor in the transmission of the HIV virus. In 1987, the National Council on Sex Addiction was created to inform the public and warn about the risks related to addictive sexuality.

In 1988, the North American psychiatrists Reed and Blaine ( 1978 ) proposed a nosological description of addictive sexuality and described a process in four phases in which both compulsive and impulsive aspects can be found:

a phase of obsession, during which in response to existential difficulties the subject is totally absorbed by sexual preoccupations;
a phase of ritualization, that is to say the execution of rituals that precede sexual behavior;
a phase of sexual activity, which leads to a temporary and provisory relief; and
a phase of despair with a sentiment of the incapacity to control one’s own behavior.

Like other forms of dependency, sexual addiction builds up through a process in which several stages can be distinguished: experimentation, occasional (festive) use, regular use, but which do not yet constitute sufficient reason to seek help. It is when this use becomes a response to existential difficulties that an addictive problematic, that is to say a dependency, and which has become a source of suffering, begins to settle in. Of these practices, the subject may say ‘It’s stronger than me/I can’t help myself.’ From a symptomatic viewpoint, one can observe a polymorphy of manifestations. The starting point is a devouring sexual need that can have various manifestations: compulsive masturbation, addiction to pornography, cybersex on the Internet, promiscuity, increase in the number of sexual adventures, addiction to chat rooms, an excessive frequenting of sex-clubs, or pick-up venues (toilets, parks, motorway lay-bys) that become the only ‘pass-time’, recourse to prostitution, picking-up, and so on. This dependency on objects or situations presenting a sexual connotation (images, places, clubs, online pick-up sites, films, etc.) invades the subject’s everyday schedule. Coleman ( 1992 ) proposed an evaluation grid to detect sexual addiction. The subjects who present at least two of the following characteristics can recognize themselves as being sex-addicts :

compulsive and unsatisfying pick-ups implying a constant and insatiable search for multiple partners;
an unsatisfying compulsive sexuality in which the other is reduced to the state of partial object;
masturbation that is compulsive (or frenetic, with a frequency of 5–15 times a day, sometimes leading to injury, irritation of the skin, an intense feeling of fatigue, or even social and/or professional difficulties);
compulsive fixation on one or several inaccessible partner(s), an idealization of the love object; and
multiple compulsive love relationships (constantly seeking intensity of feelings through new adventures).

This sexuality disorder seems to be stronger in men, in that 80% of subjects treated for sexual addictions are men. But these statistics remain empirical in the measure that there have been no epidemiological studies on the question. This neo-pathology apparently concerns roughly 3%–6% of the overall population of the United States, where it is now possible, for men as well as women, to frequent the sex addicts anonymous (SAA), an antidote to the distress of solitary sex-maniacs . In France, research in clinical psychopathology took some time to take an interest in the phenomenon. In the field of psychoanalysis, it was the works of Joyce Mac Dougall that as early as 1978 took an interest in ‘the psychic economy of addiction’. Since then, work in the field of addictology has progressively developed research, reflections, and observations on these new behaviors of dependency. Addictive sexuality is considered as an ‘addiction without drugs’, and the term of ‘compulsive sexuality’ is often employed to designate it in a larger sense. Important research poles of clinical psychiatry for the different ‘addictive practices’ today also accommodate ‘ sex addict .’

Elements of psychopathology

Phenomenological psychopathology of addictive sexuality.

From the phase of searching up until the actual sexual activity, the subjects concerned may feel some benefits: reassurance, well-being, an almost manic excitement, a narcissistic shoring-up, and sensations of pleasure. But as soon as the sexual act has taken place, certain subjects can be gripped by sadness, remorse, as well as by feelings of shame, and guilt. One fine clinical psychopathology study for that matter shows that – unlike in the schema proposed by Carnes – these reactions vary largely depending on whether the subject functions according to a neurotic, borderline, psychotic, or perverse structure. Reactions of shame, disgust, and guilt being much less frequent in the borderline, personality organization often present in these subjects. One may rather note reactions of intense depression (of a narcissistic type) when the object or situation targeted by the idealization has not been found or satisfied. The subject then feels empty and will have a tendency to identify himself with rubbish or waste matter. The negative effects are then experienced: a feeling of going round in circles, risk taking, low self-esteem, depressive elements, and associated pathologies (alcoholism, poly toxicomania, etc.). The inability to be happy in a couple relationship, repetition compulsion, giving the impression of a loss of control, and the centering of an existence that only focuses on a single preoccupation; these elements – associated with a painful sense of failure – are often at the origin of a request for treatment. It is often the sense of marginalization and loss of meaning that forces recognition of the dependency.

Time immobilized by the repetition compulsion

From the point of view of temporality, the sex-addict suffers from a repetition compulsion, often giving him an impression of a stagnant temporality that is not open toward the future. Kernberg ( 2008 ) described the characteristics of a specific type of subjective temporality within the narcissistic pathological personality organization. He distinguished the subjective temporality of neurotic subjects (tending toward the investment of a complete object) and that of subjects reduced to a narcissistic libido. It is as if the latter made great efforts to shrink or destroy time to reassure themselves with an illusion of permanence and eternity. In this configuration, it is difficult to integrate new experiences; the repetition compulsion shows that time does not pass and that it is frozen. A number of narcissistic patients ‘wake up’ at the age of 40, 50, or 60 with a desperate feeling of years lost: life has gone by without leaving a trace. The experience of shrinkage of time in these cases can lead to an intense and growing fear of death, a sense of injustice at the briefness of life as they experience it. This fear is also related to the infantile fears of abandonment and solitude. A deep sense of the pointlessness of life predominates when there is an absence of investment in love, work, ideals, children, or values. In a certain way, the non-establishment of a relationship of trust in others does not allow the development of a trusting relationship to time.

How to live without belief?

To believe, one must be able to place one’s trust not only in others but also in oneself. The etymology of the word ‘confidant’, cum-fides (with faith), says precisely this. Sex-addicts experience great difficulties in believing that they will find a response to their desires in others (Estellon, 2002 , 2005a , 2005b , 2009 , 2011 , 2012 ). Believing requires recognition of not only the power of invisible phenomena but also hope. Some of these beliefs are vital: belief in the natural functioning of one’s own body; in the continuity of the self; in the reality of the outside world; in the consciousness of others. Without that, it will be difficult to fully inhabit one’s own life. And as Freud reminds us, to love other people, one must first be able to love oneself. Subject to narcissistic fragilities and affective deficiencies that he in general would rather ignore, the sex-addict uses other people’s bodies for a fix and to forget that he no longer believes in anything much, including himself. Unlike the collector who watches over his objects by keeping them close to hand, the sex-addict ‘zaps’ from one anonymous body to another, without holding onto anything. In these practices, the sexual partner cannot exist in his identitary or historical dimension: he is an anonymous body who constitutes a palliative for the body in urgent demand of erogenous stimulation.

Relationship zapping and the anonymity of encounters

The verb ‘to zap’ makes reference to several dimensions: that of forgetting of an impatience with waiting, a feeling of boredom preceding a breaking away. The temporality of zapping is interesting in that it proceeds from a current present that is open onto an immediate future. In this posture, it is a matter of contenting oneself with fragments as they appear without worrying about the whole, of switching to something else. The notions of duration, accomplishment, of the associative link, are quite simply wiped out. Z apping functions partly through the vision. It fills the mind with images and sensations without leaving any time for actual elaboration. This temporality is characterized by an impatient present tense that wants nothing to do with waiting. Defensive strategies often lead the sex-addict to experience any durable construction – implying stability – as being mediocre or as yet another constraint. Hence, the need for constant change in order to feel free … up until the day when the subject can no longer bear his addiction to change. Engaging in a therapeutic undertaking can be the occasion for the subject to maintain a relationship in a stable rhythm as a couple, with certain overall constants. Within this complex undertaking, the aspect of the framework’s stability associated with a certain flexibility is determinant.

The space of the backrooms

If addictive sexuality is a disorder that is easier to live with in big cities than in the countryside, this is in part due to the strong urban implantation of various venues dedicated to sexual encounters: clubs, bars, baths and saunas, cruising areas , prostitution zones, sex shops, and so on. The backroom – literally ‘the room at the back’ is an isolated place in a private establishment (bar, discothèque, sex-club, sauna) that is organized in such a way as to permit the interested clients to isolate themselves to have sexual relationships in the half-dark (Mac Dougall, 1978 , 1991 , 1993 , 1996 ; Estellon 2005a , 2005b , 2012 ). After having spotted objects of interest in the soft zones (at the bar or on the dance floor), one can head toward the hard zone to get comfortable and share sex … If they have today spread to the libertine world, backrooms were born in the American gay milieu in the 1970s. Strangely, they developed just as homosexuality started to come out of the shadows, as if to pay a funereal homage to the dark, hidden, clandestine, and shameful places long frequented – for lack of choice – by homosexuals repressed by the police. Somber, damp, and strong smelling, they replaced the former urinals where sexual activity took place inter faeces et urinas . Often fitted out with minor conveniences ( slings , glory holes , cages reminiscent of the prison world, labyrinths …), they can be play areas that are appreciated by sex-addicts . In these spaces, there is no social identity, no faces, but body parts revealed by hands touching, caressing, feeling, entering. If the AIDS years led to the closing down of most of these places in the United States, it is in the major European cities that they flourish today.

Personality traits, defense mechanisms

According to different authors (Carnes, Earle, Estellon, Goodman, and Poudat) one finds certain common personality traits in sex-addicts such as:

affective insecurity;
intolerance of frustration;
a tendency to action and to acting out;
a ‘belief’ in an operative and mechanical sexual model;
the presence of a second state during the crisis;
the compulsive system;
emotional overflow;
difficulty with conjugal stability;
rational anxiety;
affective and social isolation; and
masked depression.

Certain characteristics – the invasive presence of obsessions and the prevalence of compulsive systems – have led some authors to make a link between these clinical elements and obsessive compulsive disorders. Except that to the opposite of the sex-addict , the obsessional does not take action: he fantasizes more than he takes act. The strategies of taking act and of externalization of conflict are rather reminiscent of a ‘borderline’ psychic functioning in which an escape through behavior little elaborated by a thought process is often privileged: alienated from the outside world, the ego of these subjects is easily exposed to an overflowing of emotions, breaking down, and states of distress.

The psychoanalytic clinical data of sex-addict subjects (Estellon, 2005 ; Mac Dougall, 1978 ) gives a glimpse of a characteristic psychic functioning – quite close to a borderline functioning with recourse to certain common defensive strategies.

The love/sex split

Splitting is the essential defensive operation used by sex-addicts . Its main aim is to avoid the confrontation of the subject, in the face of his affective ambivalence, with depressive suffering. Here, splitting radically separates affectionate impulses from sexual impulses. Sexual partners will be little invested affectively, whereas other people in the entourage (friends, family, inaccessible partner) are highly invested.

Complementary to splitting and shored up by it, denial permits the exclusion of the field of consciousness and facilitates the isolation of those representations or affects that are not in keeping with the ideal self-image. Everything that might fragilize the psychic life by its contradictory or ambiguous character is evacuated. A loss, a grieving process, a separation, for example, might in such subjects provoke reactions in which there is no apparent suffering. Denial shoring up the splitting, the sex-addict can, with complete indifference, leave any partner who has been imprudent enough to become tenderly attached to them. In the same way, when the sex-addict feels strangely affectionate toward a partner, reactions of distress or violence can appear.

Idealization, omnipotence, and devalorization

The mechanism of idealization functions in a way that is complementary to splitting. A new person can be strongly idealized: presenting no failings, doted with all possible qualities, they are apprehended as being ‘perfect’. Splitting allows, when the deceptions or frustrations have spoiled the perfection of this object, to denigrate them, to disdain them, and deinvest them as easily as the touch of a finger is able with a remote control to zap a boring TV program instantaneously. I am thinking of a certain patient who regularly changed sexual partners: as soon as they became frustrating, they were ‘rubbed out’ according to her expression. This is the phenomenon of devalorization. A corollary of omnipotence, it allows one, without suffering, to get rid of an object when it does not bring the expected or desired satisfaction. Splitting thus ensures that a part of the Ego remains idealized (the grandiose self) in such a way that the feelings of suffering, frustration, deception, desire, or hatred, when they are experienced, can always be imputed to the action of an ill behaving other. These charicatural reactions permit the Ego – whose frontiers are unsure – not to collapse. This defense mechanism constitutes a veritable motor for the zapping mode of functioning described above.

Anaclitic anxieties and their avoidance

From a relationship point of view, addictive sexuality can be understood as a phobic strategy that allows one to avoid any real encounter with others. One often finds at the basis of these compulsive practices two types of relationship anxiety: an anxiety of intrusion coupled with an anxiety of abandonment. Haunted by these anxieties, the problematic of attachment becomes unbearable. In such a configuration, the certainty of a breakup is preferable to the torments of its uncertainty. And, so as ‘not to lose one’s mind’ one ‘zaps’ from one body to another. The fact of systematically leaving the other, anonymous person allows one not to suffer the anxiety of being invaded and even less the worries of abandonment. Thus, one avoids the depressive suffering linked to deceptions caused by the other in whom one might have believed and to whom one might have become attached.

Seen in this optic, one better understands how the other person comes to be ‘consumed’, instrumentalized as a pleasure object. Curiously, what takes place is a reversal of the latent desires and the pragmatic and compulsive behavior: if what is subconsciously sought is love, what is requested in reality is only a matter of sex. This sexual frenzy often covers up a strong and denied affective deficiency.

Comorbid disorders and risk taking

Other dependencies.

During sexual activity, drugs may be used by the more dependent subjects: poppers, GHB, or Gamma Butyrolactone (GBL), cocaine, crystal, hashish, and so on. Currently, the most common are poppers, cocaine, and GHB, we will here describe poppers and GHB as they are more specifically used during sexual activity.

Poppers are vasodilators originally used in medicine to cure certain cardiac illnesses, containing butyl and pentyl nitrates; sniffed in a non-medical use, their effects are almost immediate: a brief, vertiginous, and stimulating high, a heightening of the internal pressure of the eye. The user feels a strong sensation of inner heat and sensuality is exacerbated. The effect of the sniff lasts about 2 min.

GHB is a very powerful anesthetic. In a liquid form, it can be drunk pure or mixed with non-alcoholic drinks. Sometimes called the ‘rapist’s drug’, GHB provokes overall relaxation, euphoria, and heightens sexual excitement. The effects depend largely on the dosage but vary from euphoria, relaxation, somnolence, deep (comatose) sleep, and unconsciousness to the loss of inhibitions, an intensification of perception, a need to talk, or slight vertigo. For lack of means, GBL (Gamma Butyrolactone, the precursor of GHB, used in industry as paint dissolver, epoxy, or nail varnish) may be consumed. In the organism, GBL turns into GHB; more dangerous; being more difficult to dose, it can provoke potentially fatal comas.

Risk taking (barebacking, HIV, STD, etc.)

Latin etymology reminds us that risk ( resecare , literally ‘to cut’) is foremost a cutting-off point. Insolent and seductive, risk taking allows one to leave behind the securized world in which one is immersed. One of the dangers linked to the chronicization of addictive sexuality comes from the risk of no longer being able to find satisfaction with the usual sensations and searching more ‘pure’ or ‘stronger’ ones: one can, for example, do away with condoms that get in the way of pure sensation, consume various drugs which, if heightening the sensations experienced, no longer allow one to evaluate certain vital risks. Barebacking (unprotected sex despite the risk of transmission of the HIV virus) is more and more frequent among sex-addicts in the gay world. On top of the risks of HIV, this practice increases the risks of contamination of various other sexually transmitted diseases that can prove dangerous if they are not detected in time (Syphilis, Hepatitis B). When he becomes interested in searching for stronger sensations, the sex-addict can direct his sexuality toward more hard-core practices (fist-fucking, bondage, SM, urophilia, scatophilia, etc.). It is in these aspects that addictive sexuality can become a source of suffering, of isolation, and marginalization. The results of the studies by Peretti-Watel et al. ( 2006 ) show that risk taking is that much higher in subjects who are depressed or vulnerable.

Masked depression

Depression often constitutes the backdrop on which sexually addictive behavior is constituted and chronicized. Whether in works on psychoanalytic psychopathology (Estellon, 2002 , 2009 ; Mac Dougall, 1978 ; Pirlot, 2009 ) or on behavior (Bancroft & Vukadinovic, 2004 ), current research makes the link between the recourse to sexual addictions and elements of narcissistic depression such as the loss of self-esteem. The loss of belief in the positive effects of a relationship, the loss of hope in others, progressively makes one lose sight of the meaning of a life that has – despite the erogenous sensations that exhaust themselves in compulsive repetition – become sad and empty.

Research in neurobiology

In this chapter, it is interesting to summarize some recent studies issued from cognitive neuroscience that investigated human male sexual behavior in general and, for some of them, its compulsive practice. Although using very different theoretical and experimental settings, sexual affiliation is for us one of the most promising context to articulate a dialog between neuroscience and psychoanalysis. Today, what do we know on the neural circuits involved in human male sexual arousal? Is that possible to identify variations within these neural processes when sexual practice is becoming compulsive ? Here are the two main questions of this section.

Recent advances from neuroimaging studies

From now several decades, the growing development of neuroimaging techniques shed light on brain processes with a new angle. It is now possible to record brain activity in a wide variety of perceptual, cognitive, or motor paradigms. In addition to a considerable increased knowledge of the brain circuits involved in general cognitive processes, two fields meet an exponential development: the so-called affective neuroscience (Pankseep, 2003 ), interested in the identification of brain networks involved in emotional and motivational informations processing and the so-called social neuroscience (Insel and Fernald, 2004 ) crystallized around the cerebral correlates of the processing of social information. These two approaches converge on questions such as the investigation of brain processing of emotional informations emitted by conspecifics. In this regard, recent studies have helped to highlight the connections between cognitive and neural systems involved in the production of the action and the perception of the action by a third party. As a good example, famous studies identified a specific group of neurons within the premotor cortex that were increasing their firing rate as well as during the production of an action as during the perception of the same action produced by a conspecific (Rizzolatti & Arbib, 1998 ).

Two emerging fields within cognitive neuroscience: affective and social neurosciences

The above-developed perspective is now extending to the topic of emotions. At the moment, empathy is one of the most studied affiliation contexts, in particular through the perception–action model coupling mechanisms it assumes (Preston, de Waal, & Frans, 2002 ). To feel an emotion when observing the same one in another person involves a physiological synchrony between the observer and the observed one (Levenson & Ruef, 1992 ). For example, to be exposed to a disgusting flavor activates the same neural structures than to observe a disgust facial expression in another person (see the example of the insula in Phillips et al., 1998 ). Insular lesions prevent both the experience of disgust and the recognition of social cues conveying disgust (Calder et al., 2000 ). Comparably, the neural circuits of nociception are activated both by real pain and the representation of the affective state of someone in pain (Morrison et al., 2004 ; Singer et al., 2004 ). These results suggest that neural structures involved in emotional information processing also participate in the intersubjectivity of interacting people. However, the recovery between activated structures is not total. This suggests a certain amount of dissociation between regions involved in self-perception and those involved in other perception. This should avoid a confusion between a ‘self’ and an ‘other’ representation and therefore, the expression of an excessive empathy, potentially maladaptive (Batson et al., 1997 ). Although a functional context such as empathy encompasses an intrinsic social component, relationships between individuals first obey to an intrinsic interattraction motivational component (that can be either positive or negative). However, this interattraction component can be studied within different functional contexts. Among these contexts, sexual behavior and its associated neural circuits has been more and more studied during last years, shedding light on interesting new results for socioaffective neuroscience. Until the end of the 90s, the investigation of mental and neural representations associated to sexual behavior was poorly studied but is now exponentially emerging. However, it has to be noted that this is mostly investigated in human males.

Sexual affiliation: a functional context between affective and social neurosciences

At the moment, an exponential number of scientific studies investigates the neural correlates of human male sexual arousal. For the purpose of this paper, we won’t establish an exhaustive list of activated areas within these different studies. Here, we would like to underline some recent results issued from socioaffective neuroscience studies that used sexual affiliation to study motivated social interactions and provided more general results.

Here, we will first focus on results obtained in healthy human males and secondly on very preliminary data from patients that could be involved in CSB occurrence.

Contemporary data on healthy human male sexual function

To understand the present assumptions of neuroscience on the neural networks that could be involved in sexual addiction, it is necessary to present some interesting recent results on the role of the brain on healthy human male sexual motivation. First, it has to be noted that functional magnetic resonance imaging (fMRI), that is, the possibility to use MR imaging to identify brain activations thanks to local blood flow variations recording, was discovered in 1993. However, the first study that used functional neuroimaging to investigate the neural correlates of human male sexual motivation used another technique (Positron Emission Tomography) and was published in 1999 (Stoléru et al., 1999 ).

In this article, we present the main results from studies with two objectives: (1) when they were published, a preliminary exploration of the neural circuits involved in sexual visual information processing and (2) to use the high specificity of this behavior as a working model to identify the neural circuits involved generally in social relations with a motivational component. Mainly, to explore the neural correlates of healthy human male sexual motivation, these studies used fMRI. Among other neuroimaging techniques, fMRI has a relatively good spatial resolution, but a quite poor temporal resolution (around 1 second instead of milliseconds regarding the classical temporal unit of the cell functions). For this last reason, fMRI is sometimes criticized regarding its ‘localisationist’ approach. Currently, an attempt that can be offered to try to overcome this pitfall is to try to unify the corresponding psychological and neural components in a neurobehavioral model.

For healthy human male, a neurobehavioral model has been proposed (Redoute et al., 2000 ; Stoléru et al., 1999 ) including: (1) a cognitive component, associated to the identification and categorization of stimuli; (2) an emotional component, related to the pleasure sensation that is linked to the pleasure associated to sexual arousal increase; (3) a motivational component, linked to the processes involved in directing behavior toward a sexually relevant target; (4) a physiological component, related to all physiological variations (i.e. genital, respiratory, and cardiovascular responses). Therefore, this is important to bring together a psychological process and a cerebral activation and to explain how these processes articulate with the other components of the model. Here, we sum up some data related to cognitive and physiological components of the neurobehavioral model.

With several decades of studies of the neural correlates of healthy human male sexual arousal, the feasibility of this scientific approach has been widely demonstrated. In other words, the presentation of decontextualized visual sexual stimuli within a scanner was valid. For example, in one of our first studies, participants reported significantly higher ratings in response to sexual visual stimuli than for neutral stimuli for the dimensions ‘beauty of the depicted character’, ‘perceived desire to engage a relation’, ‘perceived intensity of erectile response’, ‘intensity of pleasure’, and ‘interest for pictures’. Although the experimental setting and procedures were not ecological to study sexual arousal, behavioral results indicate a possible induction of sexual attitudes.

Regarding brain processes involved in visual sexual material processing, a good example is illustrated in Fig. 1 . In accordance with the hypotheses of the study, the recorded brain activations were interpreted as involved in the cognitive processes linked to motivational information processing (Mouras et al., 2003 ). For example, activations were identified in the inferior parietal lobules (IPLs; Fig. 1 , c). Interestingly, these areas were known to be activated in monkeys during visual fixation episodes occurring during environmental exploration (Lynch et al., 1977 ) and in human in cocaine users exposed to scenes where cocaine was used (Garavan et al., 2000 ). For this region, an early activation was thought, for example, as being involved in enhancing attentional mechanisms toward motivationally relevant targets. Through a more precise study of temporal activations for this part of the brain, we were able to demonstrate activations within the superior parietal lobules. In this study (one of the first fMRI studies), these activations were nonetheless sustained not only during all visual sexual stimuli presentation period but also in the early as for IPLs. These results were in accordance with a very short categorization time for sexual stimuli (Pizzagalli et al., 2002 ). Therefore, these activations were interpreted as the anatomical support of an early amplification of attentional processes directed toward visual sexual stimuli.

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Brain areas activated in response to visual sexual stimuli as compared to neutral stimuli. Notes: (A) Right hemisphere: (a) parietooccipital sulcus; (b) superior parietal lobule; (c) postcentral gyrus; (d) precentral gyrus. (B) Left hemisphere: (a) superior occipital gyrus; (b) superior parietal lobule; (c) inferior parietal lobule; (d) precentral gyrus; (e) intraparietal sulcus. These activations were obtained for a statistical threshold of p < 0.05, corrected for multiple comparisons. Figure from Mouras et al. ( 2003 ).

Source: Adapted with permission from Mouras et al. ( 2008 ).

Through published studies, a recurrent question is to know if the identified psychological and cerebral processes are specific to the functional context of sexual behavior. Importantly, the male sexual function is characterized by a highly specific physiological response, that is, the genital response. For this purpose, a specific MR-compatible device able to record volumetric penile plethysmography concurrently to cerebral BOLD responses was manufactured. Our objective was to perform correlational analyses between the genital and cerebral response’s magnitude. This was applied in two recent studies (Mouras et al., 2003 ; Virginie Moulier et al., 2006 ). It allowed to precise the involvement of a specific neuronal system in the brain – the mirror neuron system – for visual sexual stimuli processing, which means visual stimuli with a high motivational relevance. Importantly, the mirror neuron system was first discovered in monkey as a specific category of motor neurons with an increasing firing rate either during the observation of an action or the mere realization of this action. Today, the question of the involvement of this system within socioaffective information cerebral processing is one of the major debates for contemporary cognitive neurosciences.

A recent study (Carr et al., 2003 ) demonstrated the involvement of the mirror neuron system in empathy, whereas these neurons are classically known to respond to the observation of movements performed by others. Consequently, it was important here to assess the degree of implication of these mirror neurons in the observation of sexual exchange. Therefore, our hypotheses were that (1) in response to the presentation of sexual visual stimuli, the magnitude of activation of the brain networks involved in movement observation and motor imagery would predict the intensity of genital response and (2) the level of the erectile response would predict the amplitude of the BOLD response in primary and secondary somatosensory areas corresponding to the projection of the penis. Three results are developed here (see Fig. 2 and and3) 3 ) illustrating how their generalization was possible for neuroscience of social interactions.

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Parasagittal sections showing brain areas where the fMRI signal was correlated with the concurrent penile volumetric response.

Notes: X refers to the distance in millimeters from the sagittal plane. Height threshold: pb.05, corrected for multiple comparisons.

Abbreviations: BA, Brodmann area; IPL, inferior parietal lobule from Mouras et al. ( 2008 ).

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Correlation profiles between BOLD and plethysmographic signals as a function of the lag between the two signals.

Notes: The vertical axis represents the Z statistic associated with the correlation coefficient between the two signals, and the horizontal axis the lag, which is the time interval (seconds) by which the correlated values are separated. Positive lags are those where the plethysmographic response was correlated with subsequent values of the BOLD signal from Mouras et al. ( 2008 ).

The first region in which the variations in BOLD signal were correlated to those of genital response was the left frontal operculum. This region is part of the mirror neuron system that encodes the correspondence between observed events and internally generated actions promoting a link between observer and the actor (Rizzolatti & Arbib, 1998 ). In the functional context of sexual affiliation, two interpretations are possible regarding the role of this neural system: preparing to perform an activity similar to that observed and/or support of an internal representation of movement (Decety et al., 1994 ). On the one hand, these neurons may play an important role in action’s preparation (in these experiments, participants often report episodes of motor imagery usually corresponding to imagined sexual acts). On the other hand, the behavioral response was also recorded by physiological (the erectile response) and some of the efferences of the frontal operculum to the insula could be the corresponding anatomical support. Therefore, these results place the physiological response at the center of the processes involved in social relations with a strong motivational component. In addition to mirror neurons areas, the correlational analyses identified several regions pertaining to the network of motor imagery and action’s observation (Decety et al., 2006 ; Grezes et al., 2006) including the inferior parietal lobules (Decety et al., 1994 ; Stephan et al., 1995 ) and the left supramarginal gyrus (Buccino et al., 2001 ; Decety, 2001; Grezes et al., 2001 ; Hanakawa et al., 2003 ; Stephan et al., 1995 ). These results are in accordance with those showing a possible anticipatory activation of this network, that is, before the observation of motor scenes (Kilner et al., 2004 ).

For somatosensory areas, important results have been obtained. For some areas (lower part of Brodmann 2), activation preceded the genital response itself, suggesting that these areas ‘flew’ the physiological response, thereby pointing to the concept of somatosensory imagery (Porro et al., 1996 ). Everything happens as if the observation of sexual explicit scenes induced activation only in motor areas corresponding to the hand, but also in areas of the somatosensory cortex corresponding to the representation of the hand. Such processes may play a role in recognizing emotions in others by the observer (Adolphs et al., 2000 ) or in preserving the sense of self during action’s observation (Avikainen et al., 2002 ; Ruby et al., 2001 ). Finally, for other regions, such as primary and secondary somatosensory areas, some of them seemed to ‘drive’ the physiological response, whereas others are ‘driven’ by it, suggesting the existence of positive feedback loops during genital response occurrence.

Exploratory data on CSB

The exploration of the neural networks involved in healthy human sexual behavior through modern neuroimaging techniques remains recent, centered on healthy human male sexual motivation. Even if the number of studies on this topic is growing exponentially, there are still a lot of scientific questions to solve. As shown by this article, the question of the neural circuits involved in addiction is an important topic. In the field of sexual addiction, different kinds of data are now available. Today, modern neuroimaging techniques such as MRI allow using different modalities to record during the same experimental session either data regarding the anatomical properties of the brain or its functional properties through neural activations recorded in any kind of behavior. However, from one study to another, the evaluation method to assess and evaluate compulsive sexual behavior have been different.

Recently, (Miner et al., 2009 ) compared 16 healthy human males, that is, eight control participants and eight patients with a sexual addiction. To recruit patients with a certain homogeneity, authors used as inclusion criterion the CSB syndrome. In 2000, Coleman et al. ( 2000 ) listed definition criteria for this syndrome: occurrence of recurrent and intense fantasies, imperious sexual needs inducing a personal distress during at least 6 months. As explained by authors, this syndrome shares criteria with other addictions such as bulimic behavior and pathological gambling.

Although this study was the first to present data on patients with a CSB, important hypotheses have been proposed through the report of single cases. The first one is the disruption of frontal brain areas that usually have an inhibitory effect on sexual behavior and that could induce an hypersexuality. Here, the recorded informations were only anatomical. With highly specific settings, diffusion tensor imaging (DTI) gives very precise information on cerebral white matter organization and integrity. Therefore using DTI, authors compared cerebral microarchitecture in a group of patients with CSB and a group of appealed control participants. In parallel, informations were recorded from both groups through standardized questionnaires dealing with (1) intensity of symptoms of the CSB; (2) intensity of different traits related to impulsivity; and (3) skills regarding emotional regulation. Moreover, control participants and patients were involved in a ‘Go-noGo’ behavioral task dedicated to evaluate the magnitude of impulsivity of participants by testing their inhibitory skills. In this task, they were asked to push a button when a given letter appeared on a screen, hereafter called the target letter. In a first version of the task, they were asked to click the left mouse button for each occurrence of a letter that was different from the target one (83% of the trials) and to inhibit this click in response to the target letter. This first version of the task was dedicated to evaluate the intensity of impulsivity. In a second version of the task, they were asked to left click only in response to the target letter’s occurrence (17% of the trials). This second version of the task was dedicated to measure inattention of participants by measuring omission errors when they omit to left click on the mouse for a target letter occurrence.

The results of this study were very interesting. Regarding impulsivity, patients with higher impulsivity scores as measured by standardized questionnaires were more sensitive to negative emotions. For the ‘Go-noGo’ behavioral task that indexed impulsivity, patients made more commission ( t 14 =3.09, P <0.008) and omission ( t 14 =2.69, P <0.018) errors during the condition where the target letter was presented frequently and, globally, made more errors than the control group for both conditions (commission errors: t 14 =2.98, P <0.01; omission errors: t 14 =2.76, P <0.014).

Regarding anatomical data, two different types of analyses have been performed. Globally, the patients demonstrated a ‘‘low diffusivity’’ (one of the indexes calculated by DTI and indexing the white matter integrity) that was lower in a particular zone of the frontal lobe, the superior frontal cortex. These results were changing a little bit when correlational analyses were performed between anatomical and cerebral data: a negative correlation was demonstrated between anatomical parameters and either impulsivity or negative emotion sensitivity for the inferior frontal cortex. How to interpret these results?

Firstly, these results demonstrate that CSB shares a lot of properties with other impulsivity control disorders such as kleptomania, pathological gambling, and alimentation disorders. Thanks to the Go-noGo behavioral task, a higher level of impulsivity was reported in patients with CSB than in control participants. These results are in accordance with those demonstrated in patients with compulsive obsessional troubles as reported in a recent study using the same behavioral task in a group of patients depicting trichotillomania as compared to controlled participants (Chamberlain et al., 2007 ).

The cerebral side was also explored in terms of anatomy and processes. The anatomical data did not support the first hypotheses of the authors. Indexes calculated by DTI did not show any significant difference between patients with CSB and control participants. These results were different than those of previous studies reporting a disorganization of the inferior frontal cortex in other categories of impulsivity disorders (Grant et al., 2006 ; Hoptman et al., 2002 ; Rüsch et al., 2007 ). Although no significant results were reported, some preliminary tendencies regarding anatomical data appeared. DTI indexes variations were reported for the superior frontal lobe between patients and control participants that supports an alteration of axons within this region. For neuroimaging, a very interesting approach is to perform correlational analyses between neuroimaging and behavioral data. For this specific study, authors demonstrated a correlation between impulsivity measures and white matter troubles for the inferior frontal gyrus. Similar results were demonstrated in studies dealing with compulsive obsessional disorders.

As explained above and as postulated by Eli Coleman (1992), CSB would be a partial response to negative affects such as depression or anxiety. Such an hypothesis is in accordance with responses reported in patients with higher ratings on a negative emotional scale and with behavioral and anatomical data recorded more generally in anxious troubles. As mentioned above, anatomical data would support CSB more as an obsessional compulsive behavior than an impulsivity control disorder.

Therapeutic

Clinical and therapeutic difficulties.

Clinically, this type of addiction raises the problem of its screening. Indeed, to consult a therapist because of a too intense sexual like is not trivial. Moreover, the denial of the problems related to this kind of behavior, avoidance of suffering of depressive symptoms associated with a personal questioning do not help much these patients to consult a therapist. When a therapeutic process begins, it will promote a flexible but robust therapeutic setting so that the patient gradually learns to keep a rhythm that is to say, also invest in the therapeutic relationship rather than to go from on therapist to zap from one therapist to another one as soon as frustration is felt. Emotional reactions on edge, acts, or acting out often make it difficult to develop a good psychic elaboration.

Behavioral individual or group SAA therapies

Carnes ( 1989a , 1989b ) was the first to develop a behavioral method based on the 12 steps of Anonymous Alcoholics that aims to rehabilitate these individuals. The method is quite simple: it offers targeted groups complete abstinence regarding sexual behavior. Other authors such as Earl ( 1995 ) developed care programs in the same direction. Schneider ( 1991 ) highlighted the difficulty of these individuals to stop their behavior: the individual suffers from the same withdrawal symptoms as the one who continues to consume alcohol and drugs such as anxiety, insomnia, tremors, headache, and a depressive syndrome. This simple idea has some merit to attract patients, who, desperate and alone, then have a new challenge to overcome. Indeed, abstinence will be able to afford to give, eventually, relief to a later love affair, which would – before – not resist to the temptation to change automatically (because the other, that is, the partner, did not exist as such), but is the internal psychic structure really modified by this conditional abstinence?

Issues of psychodynamic therapies

The challenge for an analytical therapy is not to focus on the symptom. Thus, the final objective won’t be abstinence per se but rather a solution that suits the subject, found by him, giving him the opportunity to break free of his shackles. This type of care in the sense that such treatment will involve to be confronted to difficult life episodes, scarrying when it comes to open conflict and painful memories for consciousness. Moreover, as for some borderline states, the analytical cure for sex-addicts often reveals a great difficulty in remembering the past, which does not facilitate the elaboration processes. Behaviorally, which is implicitly aimed in the cure is learning a relationship with the other. Within the model of the therapeutic relationship (stable, rhythmic, challenging), the subject will learn a relational kind of consistency that he will be able to appreciate and incorporate the side of his emotional and sexual life. These psychotherapies may, depending on the intensity of pain experienced, be coupled with a medical care.

Pharmacological aspects

On the pharmacological side, treatments are various and depend largely on their effect on the patient: anticonvulsant molecules, hormonal therapy-reducing libido, serotoninergic antidepressants (clomipramine or selective inhibitors of serotonin reuptake), mood stabilizers and anxiolytics can be prescribed. Inhibitory hormonal therapy (often designed as castrating) is usually reserved for a forensic use. A recent study by Gulsun et al. ( 2007 ) shows the positive effects that clominpramine has on the status of patients with compulsive sexuality.

On the neurobiological side, as shown by the data discussed in this article, the investigation of the role of the brain in emotions and motivations remained for a long time out of the range of cognitive neuroscience. A fortiori, it took a decade after the discovery of an imaging technique such as functional MRI to see the first studies on male sexual behavior appear. Although developing exponentially, the field remains largely unexplored for healthy sexual behavior. For sexual addiction, neuroscientists still have little data. However, these data are encouraging and suggest that the disorder observed on the behavioral side resonates with that observed on the neural side. The sexual affiliation model and its associated troubles could become one of the most second working model for the convergence and the dialog between psychoanalysis and neuroscience. Regarding therapy, these new addictions called ‘drug free addictions’ just began to be recognized and treated. Large clusters of research centers in clinical psychiatry are at the forefront of current research on these different ‘addictive practices’ and now host ‘sex addicts.’ These new clinical configurations are an opportunity for clinical psychopathology invited to rethink some of its theoretical and technical cares. Clinical and scientific advances in this topic are of great interest for other fields (sociology, anthropology, epidemiology, and public health) in terms of their impact in reducing risk for HIV prevention.

Conflict of interest and funding

The authors have not received any funding or benefits from industry or elsewhere to write this review.

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November 17, 2017

Understanding the roots of sexual addiction.

Written by By Ramon Ivey, MS, Licensed Marriage and Family Therapist

Sexual addiction and compulsive sexuality is the fastest growing addiction in the world, according to many of the top experts in the field. There are many reasons for this including, but not limited to, the ease of access, perceived anonymity, and affordability associated with the rise of the internet.

Most people have someone in their life that they can reference who has had their relationships and families torn apart due to their sexually compulsive behaviors. In fact, statistics suggest that forty percent of married couples have experienced conflict in their marriage directly related to the viewing of pornography. In addition to those we may know personally, there are a host of celebrities who have been exposed and suffered great consequences for their sexual exposés. Due to the public nature of many of the people impacted, sexual addiction and its remedies have become a regular part of public discourse. As such, I have heard these conversations everywhere from the local pub to the local church. From the local news to AM talk radio. No matter where I hear these topics being discussed, it often seems that they are presented with the utmost of authority, intensity and dogma as if the speaker was in the throws of defending their dissertation on the subject. Not surprisingly, the “solutions” presented in those conversations seem to be just as varied as the host of characters who are imparting their “wisdom.”

Some of the “solutions” that stand out in my mind as the most memorable are: “There is no such thing as sexual addiction;” “If that’s an addiction that’s the one I want;” “They just need to have more sex with their partner;” “They just need to stop!;” “They need to seek God and get their spiritual life in order;” “They need to pray harder;” or, my personal favorite, “You can’t expect the human species to be faithful to one partner!” Although some of these arguments have more merit than others, none of them really grasp how dark, lonely, divisive and destructive sexual addiction can be to the one entrapped in its clutches. Nor do they understand the complexity of the addiction and what it takes to get free from it.

Sexual addiction impacts the one entrapped on an emotional, relational, and spiritual level. The most common experience of the addict, no matter the consequences of their actions, is a “pull,” back towards their compulsive behaviors. The sexual addict finds themselves in a cycle that is commonly known as the “Addiction Cycle.” This cycle begins with the addict’s faulty belief system, which often has its origins in experiences that greatly pre-date the behavior that is currently being engaged in. The beliefs the addict often holds deep within their psyche are: personal beliefs, such as, “I am flawed and unworthy of love;” relational beliefs, such as, “If people knew me they would not love me;” beliefs about needs, such as, “My needs will never be met if I have to rely on others;” and sexual beliefs, such as, “Sex is my highest need.”

This belief system feeds into the next stage of the cycle, impaired thinking. A common, impaired thought, could be, “I can’t tell of who I am so I need to rely on myself to get my needs met.” The faulty belief system and impaired thinking send the addict into the throws of the addiction cycle, which is the addiction itself. The steps involved are preoccupation (with sexually compulsive behavior), ritualization, compulsive behavior and despair. The despair often comes from not living up to one’s own value system and realizing the addictive behavior did not meet the needs that the person struggling with addiction had hoped it would. This leads to an increased level of shame. And, as the addict stays stuck in this cycle, over time, it leads to increasing unmanageability in their life and, thus, sinking further into the addictive behavior.

As you can see from the above cycle, sexual addiction is a multi-faceted problem that impacts every aspect of the human experience; emotional, physical, sexual, spiritual and relational. I, like others, wish there was a quick fix but to espouse to that idea is not only misinformed but also helps keep the addict stuck in the very cycle they need help getting out of. Thankfully, there is hope and help through qualified clinicians and a community of people ready to embrace those struggling with the darkness of sexual addiction.

The exposing nature of desire, sex addiction, security, and trust, quick links.

Open access
Published: 07 June 2012

Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis

Jill B Becker 1 , 2 , 3 , 4 ,
Adam N Perry 1 &
Christel Westenbroek 1

Biology of Sex Differences volume 3 , Article number: 14 ( 2012 ) Cite this article

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In this review we propose that there are sex differences in how men and women enter onto the path that can lead to addiction. Males are more likely than females to engage in risky behaviors that include experimenting with drugs of abuse, and in susceptible individuals, they are drawn into the spiral that can eventually lead to addiction. Women and girls are more likely to begin taking drugs as self-medication to reduce stress or alleviate depression. For this reason women enter into the downward spiral further along the path to addiction, and so transition to addiction more rapidly. We propose that this sex difference is due, at least in part, to sex differences in the organization of the neural systems responsible for motivation and addiction. Additionally, we suggest that sex differences in these systems and their functioning are accentuated with addiction. In the current review we discuss historical, cultural, social and biological bases for sex differences in addiction with an emphasis on sex differences in the neurotransmitter systems that are implicated.

Introduction

The path from initial drug use to addiction is often described as a downward spiral [ 1 ]. The euphoria of first use deteriorates with habituation, to be replaced with heightened incentive salience associated with the drug and the cues that predict the drug as well as dysphoria in the absence of the drug. This is followed by addiction, compulsive craving for the drug, and exacerbation of dysphoria with drug withdrawal. While this narrative may capture the changing relationship between users and their drugs over time, it fails to recognize the diverse reasons contributing to initiation of drug use, which may ultimately influence how quickly an individual develops addiction. For many, illicit drugs are initially taken for their positive reinforcing effects, such as feelings of euphoria, energy, focus or sexual enhancement (Figure 1 ). For many other individuals, illicit drug use is initiated primarily to self-medicate another condition (i.e. negative reinforcement), such as depression, anxiety, chronic pain or post-traumatic stress disorder (PTSD), just to name a few. Thus, in these latter individuals, drug use provides temporary relief and functions as a maladaptive coping strategy to deal with the alterations in reward-related processes and affective state that characterize each psychopathology.

The downward spiral from sensation-seeking into addiction. The spiral depicts individuals initiating drug use (large orange arrow) primarily due to positive reinforcement (i.e., seeking the hedonic effects of drugs, such as euphoria, increased energy and alertness, or “the thrill,” which are indicated by yellow shading), which are attributed to acute increases in dopamine (DA, green arrow), norepinephrine (NE, yellow arrow), endogenous opioids (ENK/END/EM, light blue arrow), and acute increases in acetylcholine (ACh, orange arrow). A post-intoxication “crash” follows these acute positive effects due to an “over-correction” by compensatory mechanisms leading to a transient dysphoria (blue-grey shading), which is largely attributed to reduced DA function, ongoing NE activity, and increased dynorphin (DYN, dark blue/purple arrow) and corticotropin releasing factor (CRF, pink arrow) signaling. Neurochemical function and affective state eventually normalize during drug-free periods (white shading between grey arrows). Following repeated use, drug-induced adaptations can also result in the development of psychopathologies and physical symptoms that further reinforce drug use out of negative reinforcement (as depicted by the transition in the spiral from blue to red). A larger proportion of men compared to women may initiate drug use for their positive effects. However, sex differences in the highlighted neurochemical systems may also lead to different trajectories from sensation-seeking toward dependence in men and women. (The magnitude of neurochemical responses is indicated by the relative sizes of the arrows, refer to text for details on sex differences). Modified from Koob and Moal [ 1 ].

While the basic neural systems involved in positive and negative reinforcement, are similar in males and females, sex differences are present in how these neural systems are organized, activated and connected with the rest of the brain, and these are postulated to underlie sex differences in the path to addiction. Additionally, sex differences in these systems and their functioning are accentuated with drug use and the progression towards addiction. There is an extensive body of literature concerning the neural systems contributing to the development of addiction. In general, the monoamine systems (e.g., dopamine (DA) and norepinephrine (NE)), neuropeptides (e.g., corticotropin-releasing factor (CRF) and the endogenous opioid peptides) and others (e.g., acetylcholine (ACh)) have been shown to participate in either the rewarding effects of abused drugs or their negative effects observed during withdrawal. With the exception of the DA system [ 2 – 4 ], little attention has been paid to sex differences in these other systems and how they might differentially contribute to the risk of addiction in males and females.

It is the thesis of this review that sex differences exist along every aspect of the spiral pathway towards addiction. In addition, we propose the existence of a second “steeper” spiral, for which initiation of drug taking occurs to alleviate self-perceived symptoms of (stress-related) psychiatric disorders. There are sex differences in why men and women enter onto the path that can lead to addiction. Men and boys are more likely to engage in risky behaviors that include experimenting with drugs of abuse primarily for their positive reinforcing effects. In susceptible males, they are drawn into the spiral that can eventually lead to addiction. Women and girls are more likely to take drugs to reduce stress or alleviate psychological distress (e.g., depression and PTSD), thus they enter into the downward spiral already burdened with neurological changes that may promote their transition to addiction more rapidly. We propose that neither mode of entry into the spiral is exclusive for men or women, but rather, different proportions of men and women enter through the two spirals. Our thesis is that in the presence of stress-related psychopathologies, or border-line disorders, the transition from drug use to dependence will be faster. In addition, sex differences in the underlying neurobiological mechanisms of these disorders interact with the effect of drugs of abuse to result in sex differences in the consequences of drug use and abuse in a more vulnerable population.

We begin with an historical overview of evidence for sex differences in addiction and drug abuse in humans. This is followed by descriptions of the effects of drugs of abuse with initial drug use, consequences of chronic drug use and several of the brain systems involved. Sex differences will be illustrated throughout each section. We will focus mostly on the psychostimulants and opiates.

We hope this review will accomplish at least two objectives: 1) highlight the seemingly ubiquitous presence of basal sex differences in nearly every system implicated in addiction, and 2) reveal the shocking lack of knowledge of how these differences contribute to divergent (or similar) responses to drugs of abuse and the development of addiction in males and females.

Historical background

The history of use of psychoactive drugs is found throughout our recorded history. One of the first recorded uses is in the Odyssey by Homer from the 9 th century B.C. where Helen, daughter of Zeus, gave a drug that is thought to be opium to Thelamachus and his men so they could forget their grief at Odysseus’ absence, "it entered into Helen’s mind to drop into the wine that they were drinking an anodyne, mild magic of forgetfulness. Whoever drank from this mixture in the wine bowl would be incapable of tears that day… The opiate of Zeus’ daughter bore this canny power. It had been supplied her by Polydamna, mistress of Lord Thon in Egypt…" p. 59 [ 5 ]. Of course this passage records the use of both wine (alcohol) and opium, pointing out that men and women have also been using and abusing alcohol throughout our history, as well as that opium was traded even during the time of Odysseus.

It is difficult to determine the extent that women were using or becoming addicted to drugs throughout the centuries, since most of recorded history focuses on men. We know that men used drugs and became addicted, but to what extent and under what conditions have women suffered from addiction in the past? Quantitative data on the number of people (men or women) addicted to any drug do not exist before late in the twentieth century. Qualitative data about the causes of drug use and addiction are colored by perceptions of the roles of men and woman in society at the time. We relate the historical evidence for drug use by women, to contextualize the differences in the path to addiction for women vs. men.

What we know of historical patterns of drug use comes mostly from the United States where attempts to document use in both men and women began in the 1800 s, although there are anecdotal reports as well as characters in literature that contextualize drug abuse in other cultures throughout the years, as illustrated by the quote from The Odyssey above. More recently, the United Nations Office on Drugs and Crime has published annual reports on drug production and use throughout the world, but these reports are not stratified by sex/gender, and there are large populations for which data are missing. For example, in China and Africa there are no data on drug use among school age individuals [ 6 ].

Prevalence of drug use in women

The use of alcohol is recorded throughout history as an anesthetic, antiseptic and medication, as well as for its use in beverages. In plays of the ancient Greeks, women were frequently depicted as intoxicated, and drinking wine was linked to sexual promiscuity in women [ 7 ]. Throughout the ages ethanol was used by both men and women, but brewing was considered a female domestic trade in Germany, until the late 1600 s when the trade became taxed and then men took over the practice [ 7 ]. In England in the 1700 s the overuse of distilled alcohol became a “woman’s problem”. Prior to the 1700 s most alcohol consumed in England was ale, beer or wine, and these tended to be consumed more by men, perhaps because of the establishments in which spirits were consumed. With the arrival of distilled liquors in the 1700 s, gin became known as the woman’s drink, which fueled the ‘gin craze’ in England. Women were selling gin and drinking gin, gin was sold in places where women congregated and here women were selling gin to other women. While it is difficult to get quantitative data from the eighteenth century, there was a clamp-down on gin sales in 1738 and 75% of the gin-sellers appearing before a magistrate were women [ 8 ]. Female use of gin was made a social problem with a number of highly publicized cases that lead to tighter restrictions and higher taxes on gin, which further reduced use for both men and women, but women in particular.

As discussed in Brownstein (1993), the cultivation of poppies to obtain opium began with the Sumerians living in what is now Iraq during the third century B.C., although opium was being obtained from poppies before that time. From the literature one can trace to the 13 th centuries the trading of opium in Europe and Asia minor, and reports of addiction can be found in manuscripts from the 16 th and 17 th centuries [ 9 ]. The British went to war with China in 1839 and again in 1856 for the right to continue to sell their opium produced in India to China, these became known as the First and Second Opium Wars. China lost both wars and was forced to open its borders to unrestricted trade and to permit non-Chinese individuals into mainland China [ 10 ]. The active ingredient in opium was isolated in 1806 and was called morphine after the god of dreams Morpheus [ 9 ]. With the isolation of the active compound, more uses for the drug were introduced, and both doctors and pharmacists dispensed medicines that contained opiates for a multitude of ailments resulting in addiction for men and women [ 11 ].

The best quantitative data of a historical nature on women and drug abuse are on the opiates and solutions containing opiates. In the 1800 s it was widely acknowledged that in the USA more women than men were addicted to opiates (opium, morphine, laudanum or heroin). This sex difference in opiate use was quite dramatic with estimates ranging from 66% to 80% of the opium users being women during the late 1800 s [ 12 ]. As discussed by Kandall (1999) it was hard to get an accurate estimate of the number of women who were addicts in the 1800 s, because women tended to use opiates clandestinely, self-medicating with doses that allowed them to continue to function. In fact women frequently used opium for years without the knowledge of their husband, friends or family. Many physicians considered opium addiction among women to be an upper class affliction, but in fact, when doctors were surveyed in a more systematic manner there was no distinction by class, occupation or regional location. Housewives, prostitutes, women in rural farming communities, women living in Massachusetts or Alabama, all were more susceptible to opiate addiction than were their male counterparts. This was in large part because physicians and pharmacists freely over prescribed and dispensed legal opiates [ 12 ]. Furthermore, the readily available patent medicines contained large amounts of opiates and alcohol, and this contributed to their widespread use throughout the country. Doctors at the time concluded that, “women were more prone to opium addiction because of their ‘more nervous organization and tendency to hysterical and chronic diseases’” (Hamlin, 1882, as cited in Kandall 1999, p.29).

By the early 1900s there were approximately 50,000 opiate-containing patent medicines available in the USA [ 13 ]. Then, in 1906 the Pure Food and Drug Act was passed, and this law is credited with resulting in a dramatic decrease in drug addiction throughout the country. This is the law that created the Food and Drug Administration (FDA) which required that the FDA approve drugs intended for human consumption, that certain drugs be available only by prescription, and that drugs that were habit forming needed to be labeled as such (Pure Food and Drug Act of 1906, United States Statutes at Large (59th Cong., Sess. I, Chp. 3915, p. 768–772)). This law effectively put the patent medicine industry out of business, since when these medicines were tested they were not approved for sale by the FDA. Then, in 1914 the Harrison Tax Act was passed, and this law effectively limited the non-medical use of narcotics (opium, morphine and its various derivatives, and the derivatives of the coca leaf including cocaine) by imposing a prohibitive tax on all non-medical sales of these drugs 1 . All over the country, the ready access to addictive patent medicines was eliminated and drug addiction in both men and women declined. For women, the result of the Harrison Tax Act was that the proportion of women narcotic addicts declined to 50% of the population by 1918, and the proportion continued to decline until women were approximately 25-30% of addicts in the USA by the beginning of World War II [ 13 ].

This example, considered with the use of ethanol in the 1700 s in England, illustrates that when social conditions allow for easy access to a drug of abuse women can be more likely to escalate use to addiction than are men, perhaps due to the tendency to self-medicate. When restrictions are tightened, use by women falls off. On the other hand, one must also take into consideration the position of women in society during these times. Women were without a profession, frequently left alone, men of the times tended to value a frail and retiring personality in their women, so self-medication to alleviate physical and psychological conditions was tolerated and to some extent encouraged [ 12 ].

Other drugs

After World War II women who had been busy and employed during the war returned to the role of homemaker, and physicians began to prescribe the use of tranquilizers and sedatives to alleviate the stress and tension of the discontented housewife [ 12 , 13 ]. By the end of the 1960s two-thirds of the prescriptions for the tranquilizers Valium and Librium were to women. The drug industry at the time was also promoting the use of amphetamines as appetite suppressants, and women were consuming 80% of the prescription amphetamines in the USA. Since the 1960s the use of all addictive drugs by women has been increasing. It is still the case, that for individuals 18 or older, there are more men than women who are drug addicts. In the 2008 SAMSHA report, among youths aged 12 to 17, however, the rate of substance dependence or abuse among males was similar to the rate among females (8.0 vs. 8.1%) [ 14 ].

In the college age population surveyed in the 2008 SAMSHA report, containing both individuals attending college and an age-matched cohort, use of amphetamine was a little higher among college males (7.2%) than college females (4.8%), but somewhat lower among males in the non-college segment (6.3%) than among non-college females (7.7%). Cocaine showed a similar profile with college females (3.0%) reporting less annual cocaine use than college males (6.4%), and non-college males and females both reporting higher rates of cocaine use (9.3% and 8.7% respectively). For Vicodin (an opiate-based prescription medication) in 2008 males and females showed the same usage rate: 6.7% vs. 6.6%. Non-college females reported the highest rates of use for both sedatives (barbiturates) and tranquilizers, relative to all other groups. Alcohol use was approximately the same in males and females, with males having higher prevalence of binge drinking than females. The annual prevalence of marijuana use did not differ significantly between males and females among college students, nor among the non-college respondents [ 14 ].

The historic prevalence and pattern of drug abuse among males and females highlights a couple of points. First, availability of opiate drugs in the 1800 s and sedatives or tranquilizers in more recent times has lead to greater abuse of these drugs by women than men due to a combination of factors including physician’s recommendations, self-medication, and other social factors such as lack of education and job status (unemployed, homemaker, etc.). Since the 1960s the psychomotor stimulants (amphetamine, methamphetamine, and cocaine) have been used by women for appetite suppression and as a ‘pick-me up’. During the 1980s and 1990s the illicit use of these drugs among individuals under the age of 25 was predominantly by males. Since 2004, however, the sex difference in use of these drugs has declined and there has been no difference between males and females in stimulant use among this age group in recent surveys [ 14 ]. Overall, availability of drugs coupled with dissatisfying social conditions, stress, anxiety, and depression tends to exacerbate drug abuse and addiction in women. While such conditions can also increase drug use in men, it is our hypothesis that on the average this happens more often in women.

Finally, comorbidity of psychiatric disorders and substance abuse is substantial, 30-41% of subjects with a lifetime drug use problem suffer from at least one mood or anxiety disorder, and these associations are stronger in women than in men [ 15 – 17 ], supporting the idea that self-medication for mood disorders is a major path to addiction in women. While there are clearly cultural and social factors that impact whether a woman vs. a man will take an illicit drug and then continue to take the drug to the point of compulsive use and/or addiction, there are also biological sex differences that contribute. Furthermore, the same patterns of more rapid acquisition and escalation of drug use are seen in female rodents compared with males. We make the case that this is due to sex differences in the neurobiology of the system in this review.

Patterns of drug taking behavior in women and men

Only a small percentage (16-17%) of people who use drugs will progress to a state of dependence [ 18 , 19 ]. Sex differences have been reported in the risk of progression to dependence for several types of drugs. For example, males have a higher risk for cannabis and alcohol dependence, whereas for cocaine the risk is equal for men and women [ 19 ].

Substance abuse and dependence are both characterized by maladaptive patterns of substance use that lead to clinically significant impairment or distress (DSM-IV, [ 20 ]). The criteria that must be met for abuse include substance use that leads to problems at work, physically hazardous situations, and legal problems and/or interpersonal or social problems. The specific criteria for dependence include tolerance, symptoms of withdrawal, escalation of intake, persistent unsuccessful desire to control substance use, considerable time spent in activities to obtain or use the substance, other previously valued activities are reduced because of substance use, and substance use continues in the presence of adverse consequences [ 21 ]. When a user transitions from recreational to compulsive drug use, there is an increase in the amount of drug used daily, primarily from an increase in frequency of use rather than increases in the dose (for review [ 22 ]).

More men than women meet criteria for drug abuse and dependence, and men show a higher prevalence for dependence on alcohol and marijuana. On the other hand, even though more men than women use cocaine and psychotherapeutics, more women show dependence for these substances [ 23 , 24 ].

Prevalence of drug abuse and addiction is only one index of how males and females differ in their responses to drugs of abuse. Other characteristics of drug abuse are also sexually dimorphic, including age of drug use initiation, rate of escalation of drug use, and quantity of drug consumed. This is particularly true for the psychomotor stimulants [ 2 , 25 ], but is also true for other drugs of abuse [ 4 ]. For example, women start using cocaine or amphetamine at an earlier age than do men, the rate of drug use escalation is greater for women than for men, and when women seek treatment they are consuming greater quantities than are men [ 2 , 25 ]. In addition, women report higher craving then men, and exhibit more medical problems [ 16 ]. Although no sex differences in these aspects of drug addiction have been reported as well [ 19 , 26 ].

Why men and women or boys and girls begin using drugs is also different. The best data are for consumption of alcohol, but the same pattern of results is found for other drugs of abuse. In general, males report starting drug use for the thrill or to enhance their behavior in social situations, while girls report drug use to enhance their ability to cope with bad feelings, reduce stress, and decrease feelings of social isolation [ 27 , 28 ]. This sex difference in drug use initiation is also seen in the drugs that are initially used. For opiate addiction, males will tend to use heroin or other street opiates, while females tend to use prescription opiates first and then progress to the use of narcotics obtained without a prescription [ 29 ]. Perhaps as a consequence, heroin use is more common in men, whereas women are more prone to use other opiates, barbiturates, sedatives, and amphetamines.

Importantly, childhood abuse and neglect predicts subsequent illicit drug use in adulthood in women, but not men [ 30 ]. In women, drug use following early abuse appears to manifest as part of a generalized problem behavior syndrome that includes prostitution, homelessness, delinquency, criminal behavior and problems at school [ 30 ]. This relationship between early abuse and subsequent drug use may reflect the sex difference in the reason for drug use initiation, since women tend to be self-medicating for feeling of social isolation and stress reduction.

If one considers individuals who are incarcerated, the prevalence of substance abuse and dependence among incarcerated women is higher than for their male counterparts [ 31 , 32 ]. This may reflect the fact that the overall number of women in prison is much lower than men, and their convictions are often due to drug-related crimes. When examining participants with drug-related offenses that were placed in drug court programs, it is clear that women began using alcohol and marijuana at later ages, but tended to initiate cocaine use earlier than men. Additionally, while the time between initiation and the development of problematic use was similar for men and women for alcohol and marijuana, problematic cocaine use occurred much earlier in women [ 33 ].

Sex differences in the acute/subjective effects

With the exception of the stimulants (e.g., cocaine and amphetamine), the subjective effects of most drugs do not differ between men and women (reviewed in [ 34 ]). In the case of cocaine and amphetamine (AMPH), men often (but not always) report greater subjective effects than women [ 35 ]. This difference is most likely due to the fact that the subjective effects of stimulants vary over the course of the menstrual cycle, with men and women in the follicular phase (when E2 levels are low at first and rise slowly; P levels are low) being more similar to one another than either is to women during the luteal phase (when E2 levels are moderate and P levels are high).

There is substantial evidence that sex differences in the response to stimulants are due in large part to the fluctuations in estrogen (E2) and progesterone (P) that occur over the female reproductive cycle. For example, several of the positive subjective effects of AMPH, such as euphoria, desire, increased energy and intellectual efficiency, are potentiated during the follicular phase relative to the luteal phase [ 36 ]. Additionally, administration of exogenous E2 during the follicular phase further increases the subjective effects of AMPH [ 37 ].

In contrast to E2, the subjective effects of psychostimulants are negatively correlated with salivary P levels in women [ 38 ]. Additionally, exogenous P attenuates many of the positive subjective effects of cocaine when administered to women during the follicular phase, but has negligible effects in men ([ 39 ], but see [ 40 , 41 ]). Conversely, exogenous P also has been shown to increase the positive subjective effects of AMPH in women [ 42 ].

The role of androgens (e.g., testosterone, T) in the pattern of drug use in men and women has received far less attention than E2 and P. Similar to E2, T concentrations vary over the menstrual cycle [ 43 ]. Additionally, there are circadian and seasonal rhythms to T concentrations [ 44 – 47 ]} and several types of social experiences can modulate plasma T profiles in both sexes, including sexual arousal, winning/losing sports competitions, exposure to an infant’s cries and providing nurturing care [ 48 – 57 ]. T concentrations can be modulated by social experiences as well as by exogenous drugs in both males [ 58 , 59 ] and females [ 60 ]. Thus, the relationship between the response to drugs of abuse and circulating T is dynamic and bi-directional.

Taken together, these results suggest that if women start taking drugs such as cocaine or amphetamine to self-medicate for depression or anxiety, the stage of menstrual cycle may impact both their subjective to mood to begin with, as well as the efficacy of the drug to overcome the endogenous state. This could affect the risk for transitioning from use to dependence. It is beyond the scope of this review to cover all of psychoactive drug-induced changes in endocrine responses. We will focus on what is known about sex differences in the effects of drugs on E2, P, T and corticosterone/cortisol (CORT) in the following sections.

Animal models

In preclinical models, the subjective effects of drugs are often examined in the conditioned place preference (CPP) paradigm [ 61 ]. Female rats develop CPP to lower doses of cocaine than do males [ 62 , 63 ]. Yet both sexes show equivalent CPP at higher doses of cocaine. Reinstatement of CPP is also more pronounced in females at higher cocaine doses [ 64 ]. The strength of CPP in females is highly dependent upon ovarian hormones. Cocaine CPP is attenuated in ovariectomized (OVX) females, whereas treatment with both E2 and P (but not E2 alone) potentiates CPP [ 65 ]. No sex differences in CPP to (meth)AMPH have been reported in studies using intact males and females [ 66 , 67 ]. AMPH does not induce CPP in OVX females unless they are treated with E2 or E2 and P, an effect apparently mediated by estrogen receptor β (ERß) [ 68 ].

Sex differences in the rewarding properties of morphine have been reported, however, there are differences among various rat strains. In Wistar rats, females find lower doses of morphine more rewarding than males do [ 69 ]. In Sprague–Dawley rats, however, there is no difference in morphine CPP between males and females at lower doses, but females continue to display CPP at high doses of morphine that males do not prefer [ 70 ]. Thus, sex differences in the rewarding value of drugs of abuse (as indicated by CPP) vary with the drug, the dose and the hormone condition of the female rodent.

Drug taking behavior- effects of gonadal hormones

The amount taken and frequency of drug use are often different in men and women. In a survey of heroin addicts, men and women reported a similar frequency of heroin and alcohol use in the past 30 days; however, women reported significantly more days of cocaine use [ 71 ]. Similarly, in another survey of men and women in a treatment center, women reported higher frequencies for lifetime and current (i.e., past 12 months) use of crack/cocaine than men, whereas there were no differences in the frequencies of alcohol, marijuana or heroin use [ 72 ]. When examining sex differences in stimulant users that primarily abuse crack or powder cocaine, women reported greater frequencies of crack use than men, whereas patterns of powdered cocaine use were similar between the sexes [ 73 ]. Women also appear to be more vulnerable to escalation of drug use and show a faster transition from initial use to dependence [ 74 , 75 ].

Ovarian hormones

Evidence from studies in both humans and animals indicate that ovarian hormones modulate self-administration of stimulants and thus may influence sex differences during different phases of cocaine addiction. E2 administration to ovariectomized females affects many psychostimulant drug-induced behaviors, including self-administration [ 76 – 84 ]. For example, Hu et al. (2004) found that in ovariectomized female rats, exogenous E2 treatment alone was sufficient to facilitate acquisition of cocaine self-administration. E2-facilitated cocaine self-administration has also been found in other studies [ 84 , 85 ]. Finally, acquisition of cocaine self-administration is markedly reduced by ovariectomy, and restored by E2 replacement [ 86 ]. Sex differences and the effects of E2 are not limited to psychostimulants, and E2 has been found to also facilitate acquisition of self-administration of opioids in ovariectomized rats; females acquire faster and show a higher motivation to self-administer morphine and heroin than males [ 87 – 89 ]. Furthermore, there is no effect of castration of male rats on acquisition of cocaine self-administration behavior and a dose of E2 that enhances self-administration in female rats has no effect on cocaine self- administration behavior in males [ 90 ]. Thus, the effects of E2 on the acquisition of cocaine self-administration are sexually dimorphic.

Female rats will work harder for cocaine during the estrous phase of the cycle than during other phases of the cycle, and females work harder than male rats [ 85 ]. The finding that the motivation to self-administer cocaine is greater during the estrous phase of the cycle may be related to the finding that stimulant-induced DA release is enhanced during estrus relative to diestrus [ 91 , 92 ]. In contrast, sucrose self-administration does not vary across the estrous cycle [ 93 ], suggesting that drug taking behavior taps into a slightly different motivation circuit or that drugs of abuse are more effective at activating these neural circuits and so effects of the estrous cycle are observed.

Female rats also ‘binge’ for a longer initial period of time, take more cocaine over a 7-day access period, and show a greater loss of diurnal control over cocaine intake than do males [ 94 ]. When the role of E2 in ‘binge’ cocaine intake and subsequent motivational changes is examined, E2 treatment increases the initial binge length and enhances cocaine self-administration [ 95 ].

Patterns of hormone secretion are also altered during withdrawal from cocaine. During the first month of cocaine abstinence, cocaine-dependent women show elevated CORT and progesterone concentrations across their cycle compared to healthy controls [ 96 ]. In this same study, the authors report a reduction in negative affect at the end of the luteal phase, which may relate to findings in another study that a majority of women entering treatment for cocaine dependence were currently in the early follicular phase and were more likely to be experiencing high levels of anxiety [ 97 ]. High levels of anxiety and depression at the start of treatment are also associated with increased cocaine-positive urine tests at intake, which in turn predicts treatment retention [ 97 ]. Thus, fluctuations in hormones and mood over the menstrual cycle, which are both influenced by drug use and withdrawal, may impact patterns of drug taking, and the likelihood of entering and successfully completing treatment programs in women.

Testosterone

As described previously, androgen secretion in males is often dynamically regulated by social interactions that impact status or reproduction [ 48 , 54 , 98 – 101 ]. These fluctuations in androgens over the course of the day may influence the pattern of drug use and potential for relapse in men. The latter may be especially relevant to several drug-seeking triggers and may contribute to the overlap between sexual activity and drugs (especially as seen with the stimulants) [ 102 – 105 ]. Using real-time electronic diaries to track mood, drug craving and use, participants increasingly endorse “was in a good mood” prior to cocaine use, but not craving [ 106 ]. This is in contrast to heroin craving, which was more often preceded by negative feelings (e.g., felt “angry,” “worried,” or “sad”), among others [ 106 ]. In fact, men report relapse following positive feelings as well as a connection between feeling good (e.g., from winning at sports) and drug craving. Conversely, opiate and cocaine addicts are reported to have reduced T concentrations during withdrawal or while on methadone maintenance [ 107 , 108 ].

Aspects of addiction-criteria modeled in animals

Escalation of drug intake is one characteristic of addiction. The rate of drug use escalation is greater for women than for men, and when women seek treatment they are consuming greater quantities than are men [ 2 , 25 ]. The escalation of drug intake has been extensively studied in male rats. In these studies, animals that have daily access to drugs for only 1–2 h rapidly stabilize their drug intake, while animals exposed to extended daily access (>6 h/day) show increasing drug-intake over time [ 109 – 111 ]. Other reinforcement schedules can also lead to escalation in drug taking [ 111 – 113 ]. Thus, environmental conditions can influence drug-taking behavior and the preclinical situation can be made to reflect the clinical pattern of drug taking. Most of this research has been has been conducted in male rats, but females are more likely to escalate drug taking and show dysregulated intake after extended daily access [ 114 ], an effect that is modulated by gonadal hormones [ 115 ].

Persistence of drug taking/seeking in the face of adverse consequences is an aspect of addiction that is not often investigated in animal models. Rats with limited drug experience will stop responding for drugs when the drugs are paired with a stressor like a foot shock. After extensive drug taking exposure some rats will continue to respond for the drug, even when receiving a foot shock, which is thought to be related to compulsive drug taking as observed in human addicts [ 116 , 117 ]. To our knowledge no data are available for females in this regard.

Finally, that fact that only a small percentage (16-17%) of people who have used cocaine or other drugs that are abused develop dependence [ 18 ] is largely ignored in preclinical addiction research. During preclinical drug self-administration studies, the drug is easily obtained without much effort or risk on the part of the rat, so all animals learn to self-administer with stable levels of responding. When multiple addiction-like traits (i.e., high motivation to take drugs, persistence of drug seeking when no drugs are available, and resistance to negative consequences) are examined within a population of rats, only a small percentage of animals (<20%) meet all three criteria, and only after long-term chronic self-administration [ 118 , 119 ]. This indicates that chronic drug exposure is necessary to develop addiction-like behavior in rats. It is unknown whether the same proportion of female rats would meet the three addiction-like trait criteria.

Stress and craving/reinstatement of drug seeking

Sex differences in stress-reactivity are extensively reported, both in the hypothalamic-pituitary adrenal (HPA)-axis response and neurobiological consequences of stress in the brain. As reviewed recently, the relations between drug abuse and sex differences in the stress system are compelling [ 120 ]. For example, activation of the HPA-axis occurs with the administration of many different types of drugs of abuse [ 121 – 123 ], with females showing an enhanced stress response to cocaine [ 124 ]. Conversely, stress affects several aspects of drug-taking behavior [ 125 – 127 ], and activation of different components of the HPA-axis are essential for acquisition and maintenance of self-administration of cocaine [ 128 ], motivation to self-administer cocaine, sensitization to cocaine, and CPP for cocaine but not morphine [ 129 ].

Exposure to stressors induces craving in abstinent drug users [ 127 , 130 – 133 ] and thus stress plays an important role in maintenance and relapse of substance abuse. Beside stressors, exposure to cues associated with drug use also result in craving. Interestingly, these cues activate the HPA-axis and induce anxiety and subjective feeling of stress [ 133 – 135 ], indicating cues act as stressors as well. Sex differences have been found to cue and stress-induced craving. Cues associated with drugs and stress both increase drug craving in men and women; however, women appear to have a greater craving response and appear to be more sensitive to the effects of stress [ 130 , 133 , 134 ]. Neurobiological differences have also been found, with women addicted to cocaine showing a greater reactivity to cocaine-associated cues than men and a reduction in glucose metabolism in frontal cortical areas, suggesting an impaired cognitive control after exposure to cocaine-cues [ 136 , 137 ]. Interestingly, corticostriatal-limbic hyperactivity was linked to stress-cues in women and drug-cues in men, indicating a differentially activated, but overlapping, circuitry for craving in men and women [ 137 ]. The impact of cues and stress on craving appears to depend on the stage of the menstrual cycle, with decreased craving and anxiety being associated with higher P levels during the midluteal phase [ 138 ].

Reinstatement of cocaine-seeking in rats is used as a model for cocaine-craving in humans. Estrous females show greater responding on the first day of extinction training when the reward is no longer available and show greater cocaine-induced reinstatement of cocaine-seeking compared to proestrous and diestrous females, which is associated with low levels of P [ 139 ]. E2 affects cocaine-induced reinstatement in ovariectomized animals and augments cocaine-seeking. Sex differences in the amount of cocaine-seeking during the first days of extinction training have been reported, with females displaying greater amounts of seeking than males, and there are also effects of the estrous cycle on cue-induced reinstatement [ 140 , 141 ].

In rats (similar to in humans), stress enhances self-administration and reinstatement of drug-seeking for several types of drugs of abuse in both males and females [ 142 ]. Sex-differences in the effects of stressors on reinstatement are also seen in rats, with females having greater stress-induced reinstatement of cocaine seeking than males. In addition, the estrous cycle modulates the effects of stress, with proestrous females displaying higher levels of stress-induced reinstatement of cocaine-seeking [ 140 , 141 ].

Underlying neurobiology

The neural circuitry contributing to drug use and the development of addiction has been the subject of several recent reviews [ 143 – 146 ]. Therefore, we will only provide a brief overview to provide context for the sex differences described in the following sections. The vast majority of research regarding the effects of abused drugs and the neural changes underlying dependence has been focused on neurotransmission within and between the frontal cortex (Fcx), nucleus accumbens (NAc), dorsal striatum (DS), central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BST) (Figure 2 ).

The central pathways of addiction and their associated neurochemical systems. A. Sagittal rat brain section depicting the systems involved in reward/aversion and addiction. B. Medium spiny neurons (MSN) are the primary sites of synaptic integration in the DS/NAc, which regulate locomotion and reward processes. Striatonigral MSN (DYN), are essential for the reinforcing effects of drugs, whereas striatopallidal MSN (ENK) oppose the actions of striatonigral MSN and promote aversion. Cholinergic interneurons provide ACh in the DS/NAc, which is critical for regulating the balance between striatonigral and striatopallidal MSN (among other functions). The CeA/BST contain several neuron types expressing neuropeptides (and other neurotransmitters). CRF and DYN neurons contribute to negative affect, whereas ENK neurons contribute to positive affect. DA neurons in the SN/VTA send projections throughout the forebrain, which convey motivational salience and value, as well as providing an alerting signal for stimuli with potential significance. NE neurons in the LC/NTS send projections throughout the forebrain, which enhance attention and arousal and modulate systems critical for maintaining homeostasis. C. The cycle of drug abuse/withdrawal alters the balance of signaling in the DS/NAc and CeA/BST. Individuals initiating drug use primarily for “sensation-seeking” (refer to Figure 1) or “self-medication” (refer to Figure 5) have different neurochemical profiles in the basal state and during acute intoxication and the post-drug “crash.” The relative size of the pie pieces (e.g., DYN, ENK and CRF) indicates the predominance of each system, whereas the shading density (e.g., DA and NE) indicates the relative extracellular monoamine concentrations. Neurochemical profiles are further altered during dependence, with plasticity mechanisms in the DS/NAc potentiating striatonigral circuits driving compulsive drug-seeking behavior (indicated by the raised pie wedge). The collective neurochemical changes and their associated effects on DS/NAc and CeA/BST neurotransmission contribute to more frequent cycles of abuse and relapse that are the hallmarks of the spiral to addiction (refer to Figures 1 and 5 ).

In this review, we will primarily be focusing on sex differences in the DS/NAc and CeA/BST, as these regions are linked to the positive reinforcing effects of drugs, patterns of drug use and the negative experiences associated with withdrawal [ 147 ]. Neurotransmission within the DS/NAc and CeA/BST is influenced by DA and NE signaling originating primarily from within the substantia nigra pars compacta (SN), ventral tegmental tegmental area (VTA), locus coeruleus (LC) and nucleus of the solitary tract (NTS), which is largely thought to underlie the effects of drugs on motivation, attention and affect (Figure 2 ). While these brain regions contain multiple classes of local and projection neurons with diverse phenotypes, we will be focusing on DA, NE, the endogenous opioids (e.g., dynorphin, DYN and enkephalins, ENK), CRF, and ACh, as there is widespread evidence of basal sex differences in these neurochemical systems (Figure 3 ), which may become altered/exacerbated by drugs and contribute to sex differences in the development of addiction (Figure 4 ).

Sex differences in basal neurochemical systems involved in reward, aversion and addiction. A summary of the published information about sex differences in the neurochemistry of the reward system appears in this figure [ 193 , 225 , 226 , 228 , 269 , 329 , 330 , 332 , 353 , 354 , 356 , 370 , 384 , 392 , 423 , 430 , 434 , 435 , 480 – 521 ]. Abbreviations are as follows, (R): data collected from rodents; (H) data collected from humans M: male, F: female, for other abbreviations see list.

Sex differences and the influence of gonadal hormones in the effects of abused drugs. The contents of this figure complement Figures 1 and 5 and emphasize sex differences (when known) and hormone effects (when known) in the effects of drugs of abuse (as depicted in the figures) with initial drug use without preexisting psychopathology (euphoria-seeking), initial drug use when using as self-medication, and during dependence. Yellow shading indicated changes associated with euphoria/positive effects, and blue shading indicated effects associated with dysphoria/negative symptomatology (M: male, F: female, for other abbreviations see list).

The GABAergic medium spiny projection neurons (MSN) in the NAc and DS comprise one of the primary sites of integration for cortical, thalamic and limbic afferents, and in turn exert enormous control over voluntary actions and the reinforcement of motivated behaviors. MSN are segregated into two major classes based on the their patterns of axonal projections (i.e., the “direct” striatonigral and “indirect” striatopallidal pathways), electrophysiological and neurochemical properties, and receptor profiles [ 148 – 152 ]. The striatonigral MSN preferentially express D1 receptors, dynorphin (DYN) and substance P, whereas striatopallidal MSN preferentially express D2 receptors, adenosine 2A receptors and enkephalin (ENK). There is also a sub-population of “mixed” MSN that co-express D1 and D2 receptors, DYN and ENK and send projections in both the striatonigral and striatopallidal pathways; however, the exact roles of these neurons in basal ganglia function are still being clarified [ 153 , 154 ].

The dynamic opposition of striatonigral and striatopallidal MSN is thought to underlie their contributions to action selection [ 155 ]. Striatonigral MSN disinhibit downstream motor circuits (hence there being called “go” neurons), whereas striatopallidal MSN generally inhibit motor activation (hence the term “no go” neurons). Striatonigral and striatopallidal MSN in different subregions of the striatum (e.g., DS and NAc) receive unique patterns of inputs from different cortical, thalamic and limbic regions, and in turn modulate distinct aspects of action selection and form specific processing loops for motor, limbic and cognitive processing [ 156 , 157 ].

The distinct neurochemical and receptor profiles of the striatonigral and striatopallidal MSN has enabled the generation of transgenic mice in which each pathway can selectively be activated or silenced (reviewed in [ 158 , 159 ]). These models have provided experimental validation of basal ganglia models of action selection, as well as providing insights into how drugs of abuse influence behavior. In general, it appears that striatonigral MSN activity is essential for conditioning appetitive responses for both food and cocaine rewards (i.e., CPP) and cocaine sensitization of locomotion, whereas striatopallidal MSN activity is required for aversive conditioning and behavioral inhibition (e.g., attenuation of cocaine sensitization and AMPH and cocaine CPP) (Figure 2 ) [ 160 – 164 ].

In addition to their effects on basal ganglia structures and action selection, drugs also exert a tremendous influence over neural circuits regulating motivated behaviors (e.g., ingestive, reproductive and defensive behaviors), endocrine systems and the autonomic nervous system [ 165 – 168 ]. The CeA and BST are two of the more prominent structures within these circuits, which have been implicated in the effects of drugs on emotional reactivity, stress responses and affective state (Figure 2 ) [ 145 , 169 ].

The exact roles of the CeA and BST in these and other processes are still being clarified [ 170 , 171 ]. Nevertheless, certain populations of neurons, identified by their neuropeptide transmitters (e.g., CRF, DYN and ENK), often function in opposition to one another to fine-tune the output of these systems and coordinate emotional, endocrine and physiological responses to various stimuli, including drugs.

In general, the ENK neurons function as mediators of positive affect, inducing positive feelings of calm, euphoria and contentment, and promoting active stress-coping responses and recovery from stress [ 172 – 175 ]. Conversely, the CRF and DYN neurons in the CeA and BST participate in the generation of negative affect, inducing negative feelings of dysphoria, aversion and anxiety, and promote passive coping mechanisms and activation of stress responses [ 176 , 177 ]. The function of these systems are normally integrated and balanced to produce the full spectrum of affective behaviors and homeostatic responses required to navigate life’s daily frustrations and joys. However, repeated drug exposure induces plastic changes in many of these systems, which result in their dysregulation in the absence of drugs and contributes to the psychological and physical symptoms of withdrawal. Additionally, activation of these neurons by stress and conditioned stimuli (i.e., drug-paired cues and environments) may trigger anticipatory changes in affective state and homeostasis that contribute to drug craving, seeking and use [ 145 , 178 , 179 ].

In the following sections, we will discuss the roles of DA, NE, CRF, DYN, ENK and ACh in regulating the functional output of the DS/NAc and the CeA/BST and how sex differences in these systems may contribute to the different profiles of subjective effects, intake and sequelae of withdrawal in males and females.

Dopamine neurotransmission in the NAc/DS

The activity of DA neurons in the SN and VTA ranges from regular pacemaker firing to burst firing, which translate into tonic and phasic patterns of DA release that determine extracellular DA concentrations in the NAc and DS [ 180 ]. Stimuli with rewarding or salient features (or that predict rewarding stimuli) induce brief bursts of DA activity, whereas aversive stimuli typically inhibit the firing of DA neurons and reduce DA concentrations [ 181 – 183 ]. The dynamic patterns of extracellular DA concentrations resulting from these changes in activity are interpreted by MSN through the differential activation of D1 and D2 receptors located primarily in striatonigral and striatopallidal circuits, respectively [ 150 , 184 ].

All drugs of abuse increase DA concentrations in the NAc and/or DS [ 185 , 186 ]; however, their mechanisms of action can be quite different. The rapid increase in DA activates D1 receptors and biases the output of the striatum towards the striatonigral pathway. Repeated drug exposure induces DA-dependent plastic changes in striatonigral circuits that mediate their reinforcing effects on behavior (e.g., CPP and sensitization of locomotion).

The excessive extracellular DA concentrations induced by repeated drug exposure engage compensatory mechanisms that function to constrain tonic DA neurotransmission. Thus, reductions in basal DA concentrations in between periods of drug use lead to reduced D2 receptor occupancy and preferential activation of striatopallidal MSN, which may underlie the aversive (or anhedonic) state characterizing these withdrawal periods [ 187 ]. There is even evidence that D2 receptor expression is reduced following chronic drug exposure, which may be an additional mechanism to restore balance between the striatonigral and striatopallidal circuits.

Extracellular DA concentrations in the NAc and DS are regulated by the clearance of DA from the synapse by the DA transporter (DAT), which is also one of the major targets of the psychostimulants. Cocaine increases DA concentrations by blocking the DAT, and chronic drug use results in increased DAT levels and function that are thought to contribute to craving, withdrawal-induced anhedonia and binging. DAT activity was increased in the DS and NAc during withdrawal from cocaine self-administration, although there were region-specific changes in trafficking and signaling pathways regulating DAT activity [ 188 ].

While the activity of DAT appears to be increased after withdrawal from cocaine self-administration, its sensitivity to cocaine (but not AMPH) is actually reduced [ 189 , 190 ]. These changes in DAT activity and cocaine sensitivity are associated with reduced DA release, which could play a role in the development of drug tolerance, and suggest that the ability of DAT to regulate extracellular DA concentrations and serve as a drug target can be dissociated.

Sex differences in DA neurotransmission in the NAc/DS

The number of mescencephalic DA neurons has been reported to be sexually dimorphic in many species. In rats, males have more DA neurons in the SN and females have more neurons in the VTA [ 191 – 193 ], whereas in non-human primates, females are reported to have more neurons in the SN than males [ 194 ]. DA neurons in the SN often send collateral axons to multiple cortical and subcortical areas, whereas VTA DA neurons primarily innervate a single target [ 195 , 196 ]. Thus, the sex differences in the relative number of DA neurons in these areas may have functional implications in terms of connectivity and integration between cortical and subcortical processing. These sex differences aren’t observed in all laboratory rodent strains [ 197 ], which is consistent with the intrinsic variability of the SN/VTA DA neurons and response to DA manipulations across strains of mice and rats [ 198 – 201 ].

Differences in the number of DA neurons are influenced by several factors, including sex chromosome complement, the presence of the sry gene [ 192 , 202 , 203 ] and gonadal hormones [ 204 , 205 ]. Gonadal hormones also regulate the density of DA terminals in many brain regions, including the NAc and DS [ 206 – 214 ]. The effects of gonadal hormones on DA terminals in these regions are due in part to intrinsic effects within DA neurons, many of which contain estrogen receptors (primarily ERβ) and androgen receptors (AR), as well as extrinsic effects (e.g., signaling in glia and neuronal afferents) that impinge upon DA terminals and cell bodies [ 215 , 216 ].

Interestingly, subpopulations of DA neurons that project to discrete brain regions appear to have unique profiles of steroid receptors, suggesting that gonadal hormones might selectively influence regional DA neurotransmission to affect certain aspects of behavior [ 209 – 212 , 217 , 218 ]. For example, DA neurons projecting to dorsolateral DS, which is involved in sensorimotor integration, are largely devoid of ERβ and AR, whereas DA neurons projecting to associative regions of the DS express ERβ and those projecting to the NAc primarily express AR [ 219 ]. Clearly steroid receptors within DA neurons are only one avenue through which gonadal hormones can influence DA neurotransmission in the NAc and DS, as demonstrated by the robust increase in D2 receptor binding in the dorsolateral DS following E2 treatment, even though the DA neurons projecting to this region lack ERβ and AR [ 219 – 221 ].

Beyond differences in DA neuron number and terminal density, there are likely sex differences in the firing rates of DA neurons, which could impact extracellular DA concentrations in the NAc and DS. The firing rate of DA neurons in the VTA fluctuates over the course of the estrous cycle, with generally higher firing rates and more burst firing in estrous and diestrous females relative to those in proestrus [ 222 ]. The reduction in firing rate during proestrus may be caused by increased negative feedback on DA neurons (e.g., D2 autoreceptors) induced by E2 [ 222 ]. Additionally, the effects of E2 on sensitivity to DA negative feedback varies in different subpopulations of DA neurons, with some showing increased sensitivity and others reduced sensitivity [ 223 ], which may reflect DA neurons projecting to different brain regions. E2 has also been shown to alter the firing rate of DA neurons in the SN of both males and females, with both increases and decreases in activity, as well as a general synchronization of firing patterns [ 224 ]. Thus, gonadal hormones are likely to influence DA firing patterns in both sexes, with more dramatic fluctuations in females over the course of the estrous cycle.

There is evidence from microdialysis studies that extracellular DA concentrations also vary over the course of the estrous cycle and between GDX males and females, which may contribute to sex differences in the function of the striatum [ 225 , 226 ]. In the DS, basal extracellular DA concentrations are significantly lower in diestrous females compared to both males and proestrous/estrous females, which are not significantly different from one another [ 226 ]. There are also indications that women have greater basal extracellular DA concentrations in the DS relative to men [ 227 ]. Other studies in humans, however, report no sex differences in basal DA concentrations, which is also consistent with the preclinical data (i.e., sex differences only during certain phases of the reproductive cycle).

DAT expression and function change over the reproductive cycle, and following GDX and hormone replacement, which may contribute to sex differences in extracellular DA concentrations [ 228 – 232 ]. In intact females, DAT binding in the DS is greater during diestrus compared to proestrus [ 230 ], which fits with the pattern of extracellular DA concentrations [ 226 ] (i.e., lower DA with increased DAT binding, and higher DA with decreased DAT binding). In OVX females, E2 increases DAT binding to levels of intact females [ 229 ]. Post-menopausal women also show increased DAT binding following E2 replacement therapy [ 233 ], which supports the idea that exogenous E2 can positively regulate DAT function in an E2-deprived condition, whereas it may normally function to suppress DAT function (and thereby increase DA neurotransmission) in the context of cycling hormone levels.

Fast scan cyclic voltammetry measurements of DA in the DS indicate that females have greater release and uptake parameters, relative to males, and that these do not fluctuate over the estrous cycle [ 234 , 235 ]. At low frequency stimulation, the greater uptake potential of females matches their greater release, such that DA transients are similar between the sexes; however, at higher stimulation frequencies reuptake is unable to match release producing larger evoked DA transients in females. Greater DA synthesis capacity and DAT availability have also been reported in women, relative to men [ 231 , 232 , 236 ], suggesting that sex

Collectively, these data suggest that many factors contribute to sex differences in DA function within the DS and NAc. While the absolute levels of extracellular DA concentrations in these regions might only be different during certain phases of the reproductive cycle, the temporal patterns of DA tone in males and females are quite distinct. All evidence in males suggests that their DA tone in the DS/NAc is relatively stable from day to day, which may promote a consistent balance between the output of striatonigral and striatopallidal MSN under basal conditions. The fluctuating DA tone of females, suggests that the balance between striatonigral and striatopallidal MSN may also be shifting over the reproductive cycle, with greater striatopallidal dominance during periods of low DA (i.e., diestrus and OVX). Thus, the ability of drugs to engage striatonigral circuits would face variable opposition by striatopallidal circuits depending upon the stage of the reproductive cycle.

In light of the many sex differences in these DA systems, it is not surprising that DA function is differentially affected by drugs in males and females. Sex differences in DA release to psychostimulants have been reported for humans as well as animals. Munro et al (2006) reports that men show greater DA release in the NAc and greater subjective effects to AMPH compared to women [ 237 ]. In contrast, greater DA release to AMPH has been found in women in the globus pallidus as well as striatal and cortical regions [ 238 ]. Neither study controlled for menstrual cycle, so differences could be due to the use of different tracers, regional variation among brain structures, menstrual cycle effects, as well as a combination of these factors.

Female rats show greater DA release in the DS than males in response to electrical stimulation of the medial forebrain bundle and cocaine [ 234 , 235 ]. Many sex differences in the effects of drugs on DA function are the result of gonadal hormones. AMPH-induced striatal DA release fluctuates over the estrous cycle of rats, with an augmented response during the evening of behavioral estrus compared to diestrus [ 92 ]. Administration of E2 (but not P) to OVX female rats increases rotational behavior and AMPH-induced DA release in the DS [ 225 , 239 , 240 ]. It is to our knowledge unknown if similar sex-differences and effects of E2 on morphine-induced DA release occur.

Sensitization of the DA response to repeated psychostimulant and opioid exposure has been found in preclinical studies, however clinical studies rather show the occurrence of tolerance, as in diminished positive effects of drugs and a blunted DA response to drug exposure in addicts [ 22 , 241 – 243 ]. This hypo-dopaminergic state is believed to contribute to anxiety and persistent drug seeking in drug-dependent subjects [ 242 , 244 ]. Chronic exposure to cocaine has been found to attenuate both baseline and cocaine-induced DA levels in the NAc of rats ([ 189 , 245 – 247 ], but see [ 248 ]). Sex differences have been reported for sensitization to psychostimulants in rodents, which is likely related to augmented DA responses [ 249 , 250 ], with females showing a higher level of sensitization than males. E2 increases sensitization in OVX females [ 251 – 253 ], whereas the effects of CAST and T replacement are more variable [ 249 , 252 , 254 – 256 ]. We are unaware of any studies investigating sex differences in tolerance. One could speculate that tolerance develops faster in women than in men, resulting in more rapid escalation of drug use to compensate for the attenuated positive effects of the drugs.

DA neurotransmission in the CeA/BST

DA neurotransmission in the NAc and DS is essential for shifting the balance between striatonigral and striatopallidal circuits; however, the role of DA in the CeA and BST is less clear. The monoaminergic innervation of the CeA and BST includes both DA and NE projections, with discrete subnuclei in each region preferentially receiving inputs from either DA or NE neurons, or both. Within the dorsolateral BST (a region that primarily receives DA projections), intra-oral delivery of sucrose rapidly increases, whereas quinine delivery reduces, extracellular DA concentrations [ 257 ]. Reinforcing drugs also increase extracellular DA concentrations in the BST [ 258 ]. Thus, DA signaling is likely to bias neurotransmission in the CeA and BST towards outputs that promote positive arousing, emotional and affective responses. This is also supported by the ability of DA infused into the CeA to reduce the number and severity of gastric ulcers following stress [ 259 – 261 ], which may involve interactions with the ENK and CRF systems [ 262 , 263 ].

The ability of DA in the CeA/BST to modulate affective responses are partially due to its effects on inhibitory neurotransmission within these brain regions. DA attenuates evoked inhibitory synaptic currents in the CeA and BST, through the activation of presynaptic D2 receptors [ 264 – 266 ]. Cocaine self-administration (but not yoked non-contingent administration) modifies this effect, such that DA subsequently increases inhibitory currents through a D1-dependent mechanism that persists during withdrawal [ 266 ].

It is difficult to assign these effects of DA and cocaine to discrete neurons and projection pathways, due to the numerous types of neurons in the CeA and BST [ 267 , 268 ]. It does suggest, however, that the neural systems initially disinhibited by drug-induced DA signaling that contribute to the rewarding effects of cocaine (ostensibly ENK in our model) eventually become inhibited by drug-induced adaptations in D1 receptor signaling pathways [ 266 ].

Sex differences in DA neurotransmission in the CeA/BST

There have been few rigorous studies of sex differences in DA function in the CeA and BST, especially since many studies that rely on micro-dissection techniques include additional nuclei with very different developmental origins, cell types and signaling molecules (e.g., basolateral amygdala). In gross dissections of the amygdala, males and females have similar tissue DA contents, whereas males have much greater DOPAC concentrations, suggesting that the kinetics of DA neurotransmission might be sexually dimorphic [ 269 ].

There are not many studies that have examined sex differences in DA receptor expression in the CeA and BST. Interestingly, a greater proportion of D3-containing neurons in the amygdala also co-express D1 and D2 receptors in females, relative to males, a pattern that emerges after puberty [ 270 ]. Thus, the activation of DA receptors in the CeA/BST may induce very different signaling cascades in males and females.

Norepinephrine

Nearly all drugs of abuse increase NE concentrations in several brain regions, including the Fcx, DS, NAc, BST and CeA [ 271 – 274 ]. The increases in extracellular NE concentrations can occur acutely in response to the drug (thereby contributing to the initial positive or negative drug effects), develop over the course of chronic drug exposure (thereby contributing to the transition to compulsive use and habit formation), or manifest during withdrawal (thereby contributing to craving and negative reinforcement processes).

The origins of NE afferents are located in the LC (A4 and A6 cell groups), the dorsomedial medulla (e.g., the nucleus of the solitary tract, NTS, or A2 cell group) and the rostroventral medulla (RVM, or the A1, A5 and A7 cell groups) [ 275 ]. Due to their specific patterns of inputs and outputs, the different groups of noradrenergic neurons have distinct, albeit overlapping, roles in drug use and the development of addiction.

The dynamic contributions of noradrenergic signaling to early and late phases of addiction, as well as to the positive and negative effects of drugs [ 276 ] are likely due to several factors, including the multitude of NE cell groups, their diverse array of overlapping and unique afferents and projection pathways (e.g., dorsal vs. ventral noradrenergic bundles) and their reciprocal interactions with other neurochemical systems (most notably CRF and the endogenous opioids) [ 277 – 280 ].

Knowledge about the role of the noradrenergic system in the effects of drugs of abuse comes mostly from manipulations of this system and subsequently investigating effects of drugs of abuse. The loss of the α1b-AR results in the attenuation of locomotor activation and sensitization to AMPH, cocaine and morphine [ 276 , 281 ]. It also inhibits morphine CPP and reduces oral intake of cocaine and morphine in a 2-bottle choice test. All of these effects are manifested in α1b-KO mice even though post-synaptic DA signaling appears to be unaffected in the NAc and DS [ 276 ]. The endogenous ligand mediating the effects of these drugs through the α1b-AR is unknown (i.e., either DA or NE). Dopamine β-hydroxylase (DBH) knockout mice do not exhibit CPP for morphine or cocaine, even though they demonstrate CPP for food rewards [ 282 ]. DBH knockout mice also fail to show increased anxiety following acute cocaine administration, as indexed in the elevated plus maze [ 283 ]. Both of these deficits are corrected following restoration of NE biosynthesis, suggesting that they are the result of the NE deficiency, as opposed to developmental changes in the underlying neural circuitry of reward and aversion. Additionally, pretreatment with disulfiram (an inhibitor of DBH, among other enzymes) or propranolol (a non-selective β-adrenergic receptor antagonist, βAR) attenuates the acute anxiogenic effects of cocaine in wild type mice [ 283 ]. Systemic propranolol also reduces cocaine self-administration, which may reflect its potentiation of DA overflow in the NAc and putative increase in inter-infusion interval [ 284 ]. Systemic treatment with prazosin (an α1 antagonist) attenuates the motivation for cocaine in rats trained under long-access conditions, whereas α2 or β1 antagonists are ineffective [ 285 ]. In this same study, rats under long-access conditions had significantly fewer α1 adrenergic receptors in the bed nucleus of the stria terminalis compared to animals under short-access conditions or drug-naïve rats.

In addition to these reinforcing effects, NE systems also contribute to the aversive effects of drugs, especially during periods of withdrawal. Many of the negative consequences of withdrawal (behavioral aversion and physical symptoms of distress and negative affect) are attenuated following the peripheral administration of adrenergic receptor antagonists (e.g., βAR and β2AR) [ 286 – 288 ]. Ventral, but not dorsal, noradrenergic bundle lesions attenuate opiate withdrawal-induced aversions, but neither lesion attenuates the physical symptoms of withdrawal [ 287 ].

NE neurotransmission in the NAc/DS

There are several mechanisms potentially contributing to the role of NE in the positive, or reinforcing, effects of abused drugs, which all primarily relate to the modulation of DA neurotransmission in the striatum (especially the NAc). The overall effects of NE manipulations on striatal DA concentrations are the product of both local effects within the striatum. The systemic administration of propranolol potentiates cocaine-induced DA overflow in the NAc, which is associated with enhanced locomotion [ 284 ]. The local effects of NE within the striatum are more complex. In general, activation of βAR within the NAc increases extracellular DA concentrations, whereas activation of α2AR (most likely α2A-AR) reduces NE concentrations, without affecting DA concentrations [ 289 ]. Little is know about sex differences in the effects of stimulants or opioids on striatal NE signaling. There appear to be no sex differences in basal levels of NE in the NAc and DS [ 290 ]. While DS tissue from males showed a greater AMPH-induced NE release than females during most stages of the estrus cycle [ 291 ].

NE neurotransmission in the CeA/BST

The BST may be the site of action for the aversive effects of NE during withdrawal, as β-adrenergic receptor (βAR) antagonists attenuate the aversion and some of the physical symptoms of withdrawal when infused into this region [ 287 ]. The infusion of α2AR agonists into the BST also reduces aversion and some of the physical symptoms of morphine withdrawal, which may be related to the negative regulation of NE release by α2AR autoreceptors [ 287 ]. In animals addicted to opiates, the BST is activated during precipitated withdrawal, and selective β-adrenergic antagonists attenuate this response [ 288 ]. In addition, lesions of the ventral noradrenergic bundle that sends projections to the CeA/BST and NAc, unlike lesions of the dorsal bundle that target the Fcx, attenuate withdrawal-induced conditioned place aversion [ 288 ]. Infusions of βAR antagonists into either the BST or CeA attenuate stress-induced reinstatement of cocaine seeking [ 292 ].

The activation of the BST may be downstream of increased NE release, as chronic morphine treatment increases extracellular NE concentrations in the BST, which is further increased during withdrawal [ 274 ]. Chronic cocaine self-administration alters noradrenergic signaling within the CeA/BST, including up-regulation of the NE transporter [ 293 , 294 ]. Finally, blockade of α2aAR or β1AR within the CeA prevents the development of conditioned place aversion following systemic treatment with acetic acid, even though animals still display the physical signs of pain [ 295 ]. NE levels in amygdala do not differ by sex [ 296 , 297 ], it is not known if there are sex differences in drug-induced changes in NE signaling in the BST and CeA.

NE neurotransmission in the LC/NTS

Chronic morphine exposure robustly increases TH gene and protein expression in the LC [ 298 ]. This may be related to the hyper-activation of LC neurons following drug-induced adaptations in ENK, DYN, CRF and glutamate signaling [ 299 – 302 ]. Conversely, chronic cocaine administration reduces TH-immunoreactivity in the LC and NE transporter-immunoreactivity in the olfactory bulb (a target of LC noradrenergic neurons) [ 303 ].

The LC has long been recognized as a sexually dimorphic structure, both in terms of volume, neuron number and cellular morphology [ 304 – 306 ]. LC and NTS both contain estrogen receptors (both ERα and ERβ) and androgen receptors [ 307 – 309 ]. Thus, gonadal hormones regulate the activity of LC neurons and NE biosynthesis in the LC and NTS (e.g., expression of TH, GTP cyclohydrolase (GTPCH), and DBH) [ 309 – 312 ]. Sex differences in TH expression have largely been attributed to the sex-specific patterns of ERα and ERβ, with males having more ERα and roughly equivalent ERβ expression relative to females [ 309 ]. The different patterns of ERα and ERβ may also underlie the sex-specific responses to gonadectomy, which increases and decreases TH expression in the LC of males and females, respectively [ 311 ]. Exogenous E2 reverses the effects of gonadectomy in males and females [ 311 ], as does treatment with exogenous T or 3β-diol (an ERβ selective ligand) in males [ 309 ]. Neural activation in the LC also varies over the course of the estrous cycle, with E2 reducing activation and P reversing this inactivation [ 310 ]. Even though the noradrenergic system plays a role in the effect of drugs of abuse, and sex differences in this system are well known, there is very little research investigating sex differences in the interaction between NE and drugs of abuse.

Corticotropin releasing factor

Interactions with drugs of abuse.

The CRF neurons in the CeA and BST are important for mediating the emotional responses to stress and contribute to many aspects of drug abuse, including initiation of drug taking, as well as generation of a negative affective state on drug withdrawal (Figure 2 ). CRF neurons also contribute to the effects of stress on craving and relapse due primarily to their projections to DA and NE neurons in the VTA, LC and NTS [ 145 , 313 – 316 ]. Extracellular CRF concentrations are increased in the CeA following withdrawal from cocaine, opiates, cannabinoids, alcohol and nicotine, supporting the notion that CRF mechanisms contribute to the negative symptoms associated with withdrawal after addiction [ 145 , 176 , 317 – 319 ].

The CRF projections to the LC and NTS are one component of an adaptive response that increases the activity of NE neurons and contributes to increased attention and vigilance, coordinated with anticipatory physiological responses [ 277 , 320 , 321 ]. The effects of CRF on DA neurons are complex, as CRF can increase the firing rate or potentiate negative feedback mechanisms (e.g., D2 autoreceptors) that inhibit DA neuron firing [ 322 – 324 ]. The mixed effects of CRF on DA may reflect different effects on subpopulations of DA neurons conveying different signals (e.g., motivational salience, reward value, or a general alerting function) [ 325 ]. Collectively, the effects of CRF on DA neurons may serve to interrupt behaviors mediated by striatonigral MSN and promote the transition to striatopallidal circuits for more appropriate defensive/avoidance responses.

Cocaine exposure also induces plastic changes within the VTA and the CRF projections to the VTA that result in enhanced glutamate and DA release. While stress increases CRF release in both naïve and cocaine-experienced animals, only cocaine-experienced animals display the potentiated glutamate and DA release to result in the reinstatement of cocaine seeking [ 318 , 326 ]. Interestingly, CRF preferentially induces reinstatement of cocaine seeking in animals exposed to long-access, but not short-access, cocaine self-administration. Therefore, the pattern of drug intake is an important determinant of these plastic changes in CRF signaling [ 327 ]. Females appear to be more sensitive to CRF-induced reinstatement of cocaine seeking [ 328 ], and females are more sensitive to stress-induced reinstatement [ 329 ]. The vast majority of research on CRF and addiction has been done in males, nevertheless, CRF regulation of the HPA axis is largely sexually dimorphic [ 329 – 332 ]. Additionally, the expression of CRF in females varies over the course of the estrous cycle and is positively regulated by E2 [ 329 , 333 , 334 ]. Thus, depending upon the time of day and phase of the cycle, one could obtain CRF levels that support greater activity in males, females or neither.

Endogenous opioids

For the purpose of this review, we will focus on what is known about sex differences in the endogenous opioid systems in the NAc/DS and the CeA/BST. After considering these systems, we will briefly discuss additional opioid systems that are also relevant to the effects of drugs and the development of addiction, namely the ENK neurons in the rostral medulla that project to the LC/NTS [ 335 , 336 ] and the β-endorphin (END) and endomorphin (EM) neurons located in the hypothalamus and brainstem, which send projections to the NAc/DS, CeA/BST and spinal cord, amongst other regions (ref).

Opioid systems in the NAc/DS

The striatonigral and striatopallidal MSN in the DS and NAc preferentially express DYN and ENK, respectively. While these two endogenous opioid peptides are often used to characterize the MSN populations, their specific roles in local signaling and the functional output of the striatum are unclear [ 148 ]. As MSN are GABAergic, and all three classes of opioid receptors (μOR, δOR and κOR) are coupled to inhibitory signal transduction pathways [ 337 ], they likely reinforce the inhibitory actions of MSN on their projection targets [ 338 ].

MSN are also exquisitely sensitive to endogenous opioids, which may be released from their axon collaterals or peptidergic afferents (e.g., DYN, ENK, END and EM) from other brain regions [ 339 – 344 ]. Striatonigral and striatopallidal MSN both express μOR; however, they appear to be enriched within striatonigral MSN [ 345 , 346 ]. Conversely, μOR are preferentially expressed within striatopallidal MSN [ 345 ]. Thus, the striatonigral and striatopallidal MSN have unique profiles of opioid peptides and receptors that may contribute to their different patterns of activity, regulation and responses to drugs.

Self-administration or “yoked” non-contingent heroin administration increases DYN mRNA expression in the NAc shell, but not the core or DS, and has no effect on ENK mRNA abundance in any of these regions [ 347 ]. Acute cocaine or AMPH exposure reduces DYN peptide levels in the DS [ 348 ] and increases DYN mRNA expression in the DS, but not the NAc, and has no effect on ENK mRNA in either region [ 349 , 350 ].. Chronic cocaine or AMPH administration (either self-administered or “yoked” non-contingent delivery) increases DYN mRNA expression in the DS, but not the NAc [ 348 , 351 ]. Cocaine exposure also attenuates some of the effects of exogenous DYN on excitatory neurotransmission in the NAc, which could reflect adaptations in either endogenous DYN synthesis and release and/or the expression and functional coupling of presynaptic κOR in glutamatergic terminals [ 352 ].

Sex differences in opioid systems in NAc/DS

Females have greater expression of DYN within the striatum [ 353 , 354 ], whereas males have higher expression of ENK [ 353 ]. These sex differences are not always apparent [ 355 , 356 ], which may reflect the changes in the concentrations of these peptides over the course of the estrous cycle [ 357 ]. DYN peptide levels are relatively stable across the cycle in the NAc, whereas there is a significant reduction in the DS during estrus. Conversely, the concentrations of ENK appear to be more sensitive to fluctuating hormones, as they show more robust changes in both the NAc and DS and are significantly elevated during proestrus and estrus. The differential hormone sensitivity of DYN and ENK might also explain why sex differences are found in the former even in GDX animals [ 354 ].

If the relative concentrations of DYN and ENK reflect the activity (or influence) of each projection pathway, then it suggests that the balance between the striatonigral and striatopallidal MSN may be different in males and females. Thus, striatonigral MSN activity predominates in females (as suggested by their greater DYN concentrations), which could explain the more robust locomotor responses to stimulants in females compared with males. Conversely, predominance of the striatopallidal MSN in males (as suggested by their greater ENK concentration) may contribute to their attenuated responses to stimulants relative to females.

Ovarian hormones influence the acute response of striatonigral MSN to stimulants, as OVX females treated with vehicle or both E2 and P (but not E2 or P alone) displayed increased DYN mRNA expression in the DS following a single cocaine injection [ 358 ]. Immediate early gene expression was similar in all the female groups irrespective of hormone treatment, suggesting equivalent activation of MSN by cocaine. The activity of various intracellular signaling cascades in the striatum fluctuates over the estrous cycle [ 359 ]. Thus, drug exposure may translate into different patterns of DYN and immediate early gene expression depending upon the hormonal milieu.

Opioid systems in the CeA/BST

Within the CeA and BST, there are discrete populations of ENK and DYN neurons that are critically involved in the regulation of stress responses and affective state. In general, the ENK neurons promote a positive affective state and facilitate positive coping responses, especially following stress [ 172 – 175 ], whereas the DYN neurons contribute to negative affective states, especially in regards to activating stress, anxiety and fear responses and feelings of dysphoria [ 176 , 177 ] (Figure 2 ). Many of the effects of DYN overlap with those of CRF, which may be due to the extensive co-localization of DYN and CRF in many CeA neurons [ 176 , 360 ].

The effects of abused drugs on ENK and DYN in the CeA and BST are complex. ENK and DYN neurons in the CeA/BST are activated acutely by drugs and recruited during withdrawal [ 361 , 362 ]. AMPH administration acutely increases activation of ENK neurons in the CeA and BST [ 363 ]. On the other hand, chronic cocaine administration (either self-administered or non-contingent “yoked” delivery) has no effect on DYN or ENK mRNA in the CeA [ 351 ].

Self-administration or “yoked” non-contingent heroin administration increases DYN mRNA expression in the CeA, but has no effect on ENK mRNA levels in this region [ 347 ]. Morphine treatment increases glutamatergic synaptic strength in CeA neurons, which is attenuated by the activation of δOR [ 364 ]. The changes in glutamatergic signaling and δOR sensitivity in the CeA are similar to the morphine-induced loss of ENK tone in the LC [ 299 ].

Thus, excitatory neurotransmission in the CeA is normally constrained by the endogenous ENK tone derived from the BST and amygdala [ 365 ], which may confer stress resilience and positive affect [ 172 ]. Repeated drug exposure reduces endogenous ENK tone, as indicated by the increased concentrations of δOR in synaptosomal fractions of morphine-treated rats [ 364 ], which may then contributes to dysphoria and anxiety during withdrawal.

DYN neurons in the CeA/BST send projections to the NE neurons in the LC and NTS [ 302 , 314 ]. The DYN projections activate κOR located primarily in excitatory afferents relaying sensory information, which attenuate the phasic activation of noradrenergic neurons, without altering their tonic firing rates [ 366 ]. Thus, the attenuation of sensory inputs to the LC (and ostensibly NTS) is thought to blunt the affective responses to aversive and/or arousing stimuli without affecting general arousal, which is conveyed by the tonic firing of LC neurons [ 302 , 366 ]. Blunted or reduced affect is thought to promote drug use in many individuals; however, many women report using crack cocaine specifically to “numb out and start to feel nothing,” [ 367 ].

Sex differences in opioid systems in the CeA/BST

There are extensive reports about sex differences in hypothalamic opioid peptide and receptor expression [ 368 , 369 ], which generally support greater numbers of ENK neurons and density of terminals in males in some brain regions and equivalent levels in others. Brain regions with sexual dimorphisms in opioid systems tend to be those that are enriched in steroid receptors and contain other sexually differentiated features (e.g., anteroventral periventricular nucleus) [ 368 ] and E2 increases hypothalamic ENK concentrations in both males and females [ 369 ].

Much less is known about potential sex differences in the endogenous opioid systems in the CeA and BST; however, these brain regions both contain high concentrations of steroid receptors and are sexually differentiated in terms of morphology and neurochemistry. DYN concentrations in the amygdala do not vary over the course of the estrous cycle, whereas ENK concentrations are reduced during proestrus, relative to diestrus and estrus [ 357 ]. Males have greater δOR expression in the medial amygdala (MeA), whereas the staining intensity within the CeA is roughly equal between males and females [ 370 ].

Effects of drugs of abuse

Data on how (chronic) drug use affects the opioid system in the brain are limited and even less is known about sex differences herein. Chronic drug use results in increased mRNA levels of the DYN precursor prodynorphin in the striatum and amygdala [ 347 , 371 – 373 ]. Since activation of κ-opioid receptors results in depressive-like symptoms in rats, and these symptoms are blocked by a κ-opioid receptor antagonist [ 374 , 375 ], this is though to be related to the negative withdrawal symptomatology. The hypodopaminergic state found after chronic drug use [ 187 , 189 , 243 – 247 ] could be the result of increased κ-opioid/DYN signaling, since stimulation of κ-opioid receptors decreases DA transmission ([ 376 ]; for review see [ 377 ]), and this is thought to be a compensatory mechanism to counteract the high drug-induced DA levels.

Additional opioid systems involved in addiction

The NE neurons in the LC and NTS also receive projections from ENK neurons in the rostral medulla (e.g., nucleus paragigantocellularis and the nucleus prepositus hypoglossi), which may represent sites of action for the calming and stress buffering effects of ENK and other μOR agonists. [ 302 , 335 , 378 ]. ENK/μOR signaling appears to preferentially inhibit tonic activity of NE neurons, without affecting phasic responses [ 321 , 379 – 383 ]. The inhibitory effects of ENK/μOR signaling on LC tonic activity are in contrast to the excitatory effects of CRF on tonic activity and the suppression of phasic activation by DYN/κOR signaling [ 384 ].

The effects of ENK on neurotransmission in the LC (and ostensibly NTS) are also mediated through the activation of δOR. Many ENK neurons co-release glutamate and the activation of δOR autoreceptors is thought to constrain glutamatergic signaling [ 299 ]. Morphine exposure reduces ENK expression in the brainstem and ENK levels in the LC and NTS, which leads to an imbalance in ENK/GLU signaling. During withdrawal, the loss of ENK tone may lead to excessive GLU signaling and hyper-activation of NE neurons in the LC and NTS, which contributes to the withdrawal syndrome [ 299 ].

The effects of morphine on pain perception are mediated primarily through the activation of μOR in the midbrain, brainstem and spinal cord; however, antagonism of DYN signaling actually blocks morphine anti-nociception in females during proestrus, but not in males or diestrous females [ 385 ]. The recruitment of a DYN/κOR component to the effects of morphine in females is due to the formation of μOR/κOR dimers that are relatively rare in males and increased in proestrous females. The acute blockade of E2 signaling (either through ERα, ERβ or GPR30 antagonists or the inhibition of aromatase), as well as the overnight (but not acute) blockade of progesterone receptors, significantly reduces the amount of μOR/κOR dimers in proestrous females and prevents κOR antagonists from inhibiting morphine anti-nociception [ 386 ].

Males also possess unique features of opioid signaling in the spinal cord that may contribute to sex differences in opiate addiction. The release of the endogenous opioid, endomorphin 2 (EM2), is regulated by both positive and negative feedback systems that are activated following the binding of EM2 to μOR autoreceptors in the spinal cord. In males, the activated μOR can couple with either Gs or Gi/o, which respectively enhance and inhibit subsequent EM2 release [ 387 ]. Under normal conditions, the negative feedback pathway predominates; however, following morphine withdrawal, compensatory mechanisms kick in that shift the balance towards favoring Gs coupling and enhanced EM2 release. The negative feedback system mediated by Gi/o activation is the only functional coupling that occurs in drug-naïve and opioid withdrawn females [ 387 ]. As this mechanism involves the regulation of EM2 from its terminals in the spinal cord, it is very possible that similar regulatory mechanisms operate in the ascending EM terminals targeting the NAc and CeA/BST.

Thus, while females are able to shift DYN signals into μOR responses through the formation of μOR/κOR dimers, males can take advantage of promiscuous G protein coupling to increase the gain on EM2 signaling following withdrawal from exogenous opiates. While these sex-specific processes have only been characterized in the spinal cord, it is possible that opioid systems in other brain regions might also engage similar sexually dimorphic mechanisms. As DYN expression is increased in the striatum following chronic drug use [ 347 , 371 – 373 ], the formation of μOR/κOR dimers may promote the engagement of very different signaling pathways in females, which could exacerbate or attenuate their vulnerability to addiction.

On the other hand, many studies have demonstrated greater negative symptoms in males during withdrawal from opiates and alcohol [ 388 , 389 ]. Naloxone-precipitated opiate withdrawal, which blocks μOR and endogenous opioid signaling, can produce more severe symptoms than spontaneous withdrawal [ 388 ]. While males show more severe symptoms than females during spontaneous morphine withdrawal, there is no apparent sex difference during naloxone-precipitated withdrawal. Thus, both male- and female-specific compensatory mechanisms might be compromised and masked during precipitated withdrawal, whereas the robust sex difference during spontaneous withdrawal suggests more effective mechanisms in females. The different mechanisms engaged by males and females during withdrawal might underlie the sex differences in symptom severity endorsed by alcoholics and contribute to the male bias in dependence.

Acetylcholine

Interactions with DA

The large, aspiny cholinergic interneurons represent less than 5% of the total neurons in the striatum, but provide the only source of ACh for the entire structure [ 151 , 390 , 391 ]. The distribution of cholinergic interneurons within the striatum is heterogeneous, with generally higher densities found in the DS and the lowest levels in the NAc [ 392 – 394 ]. Several other regional differences in cholinergic signaling have also been reported, suggesting an even greater complexity to the function of ACh neurotransmission across the different divisions of the DS and NAc [ 395 – 398 ].

Every element within the striatum is affected by changes in ACh due to the presence of nicotinic and muscarinic ACh receptors (nAChR and mAChR, respectively) within MSN, fast-spiking GABAergic interneurons, and glutamatergic and DA afferents [ 151 , 390 , 399 – 401 ].

ACh and DA are critical partners in regulating the functional output of MSN in the DS and NAc. This partnership is largely mediated through their reciprocal interactions, as activation of nAChR on DA terminals is a major determinant of the activity dependence of DA release [ 396 , 401 ], which can also impact the balance between the striatonigral and striatopallidal MSN [ 150 ]. These dynamic changes in ACh concentrations can thus either sharpen or blunt the signals (i.e., DA) conveying the motivational salience and value of rewarding stimuli.

Activation of D2 and D5 receptors located in cholinergic interneurons inhibits and facilitates ACh release, respectively [ 397 , 402 , 403 ]. Interestingly, relatively low doses of AMPH infused directly into the NAc rapidly increase extracellular ACh concentrations, which return to baseline levels upon cessation of AMPH perfusion. Whereas a higher dose of AMPH decreased ACh concentrations until well after the end of AMPH infusion, at which time ACh concentrations displayed a significant rebound above baseline. The initial increase following low dose AMPH and the delayed increase following the high dose of AMPH were both blocked by pretreatment with a D1-type antagonist (presumably acting through D5), whereas the initial decrease following the high dose of AMPH was prevented by a D2 antagonist [ 404 ]. Thus the magnitude and temporal pattern of the DA response may determine the effect of drugs on ACh neurotransmission. As females generally display greater DA responses to stimulants (at least in preclinical models- refer to DA section), it is possible that drug-induced ACh profiles will be sexually dimorphic (i.e., rapid increase and return to baseline in males due primarily to D5 activation, whereas females might show an initial decrease due to preferential D2 receptor activation and a delayed rebound as D5 activation takes over). Direct evidence for this sexually dimorphic ACh response is lacking, but suggested by two studies from Sousa and colleagues [ 405 , 406 ].

Self-administration of cocaine has short and long-term effects on cholinergic signaling, For example it reduces Choline Acetyltransferase (ChAT) activity in the NAc (and to a lesser degree in the DS), and after 3 weeks of withdrawal ChAT activity is still significantly reduced in both of these regions. Conversely, ChAT activity is increased in the PFC during cocaine self-administration and this returns to control values during withdrawal [ 407 ]. In addition self-administered drugs induce striatal ACh release, which is greater compared to non-contingent drug delivery [ 408 – 410 ]. In addition while the DA response remained relatively stable during acquisition of self-administration the ACh release also seemed to be more directly associated with the acquisition of self-administration. This may reflect the contribution of additional cortical or thalamic glutamatergic inputs regulating the ACh response. There are indications that ChAT activity might also be reduced in the NAc and DS of methamphetamine (meth)AMPH addicts, at least in individuals using high doses [ 411 ], which seems to correspond with the preclinical data. Alterations in cholinergic activity in the caudate are also reflected by increased vesicular ACh transporter immunoreactivity in high dose methamphetamine users [ 412 ].

Ablation of cholinergic neurons in the NAc, ventral pallidum and diagonal band shift the dose response curve for cocaine self-administration down and to the left, suggesting an increase in its reinforcing effects [ 413 ]. While these data suggest ACh neurotransmission is important in regulating cocaine self-administration, the exact locus of its effects are unknown, as the lesions preferentially targeted the ventral pallidum and diagonal band and had modest effects on cholinergic markers in the NAc. More selective lesions of cholinergic interneurons in the NAc, increase the sensitivity to both morphine and naltrexone-precipitated withdrawal [ 414 ]. The systemic administration of Acetylcholine-esterase (AChE) inhibitors, which increase central ACh concentrations, reduces morphine CPP in mice with intact cholinergic interneurons, but not lesioned mice. AChE antagonists also attenuate many of the effects of cocaine in intact mice, but not those with cholinergic lesions in the NAc, including CPP, locomotor activation and sensitization [ 414 ]. Thus, these data also suggest that ACh neurotransmission in the NAc opposes the reinforcing effects of drugs, which is consistent with the ACh-DA balance hypothesis in terms of promoting approach and avoidance [ 415 ]. It is suggested that increased striatal ACh release might contribute to the negative effects of withdrawal.

Both mAChR and nAChR are likely to contribute to the ability of drugs to condition behavior. Activation of mAChR with the non-selective agonist oxotremorine reduces cocaine self-administration, and this effect is blocked by concurrent treatment with a selective M1 antagonist [ 416 ]. Whereas antagonism of nAChR (mecamyline) reduces cue-induced cocaine craving in dependent subjects [ 417 ].

Sex differences

The preceding descriptions of cholinergic function in the striatum have largely been derived from research in males. There is however an extensive body of literature demonstrating sex differences in cholinergic function in the cortex and hippocampus [ 418 – 424 ], and many of these differences are also present in the striatum. We are unaware of any studies that have directly compared the effects of drugs on ACh neurotransmission in the striatum of both males and females, especially in relation to their reproductive hormone status. Sex differences in cholinergic function in the striatum are likely to contribute to differences in the effects of abused drugs.

There is some circumstantial evidence that the cholinergic systems of males and females respond differently to drugs. M1 and M2 receptor binding is increased in the striatum of female rats following repeated cocaine injections [ 405 ]. In male rats, repeated cocaine injections decrease M1 and M2 receptor binding in the striatum from 30 minutes up to 30 days after the last cocaine injection, including the same 24 hour time point examined in females [ 406 ]. Unfortunately, the two studies used different cocaine doses (5 and 10 mg/kg in females vs. 20 and 30 mg/kg in males); however, the striking divergence in the direction of the effects (i.e., increased in females and decreased in males), supports the contention that cholinergic signaling in the striatum may respond very differently to drugs in males and females.

Many aspects of ACh neurotransmission are sexually dimorphic (Figure 3 ); however, there are often conflicting data, which most likely reflects differences in the parameters under study (e.g., cell number, mRNA abundance, protein immunoreactivity, enzyme activity, receptor binding, etc.), not all of which are different in males and females. In the DS and NAc, the vast majority of studies suggest that males and females maintain different profiles of ACh neurotransmission.

Examinations of the effects of hormones on cholinergic markers have largely been confined to the contiguous groups of cells distributed throughout the medial septum, vertical and horizontal limbs of the diagonal band of Broca, and the substantia inominata (i.e., nucleus basalis of Meynert), which provide ACh projections to the cortex and hippocampus. Cholinergic neurons in these regions show reductions in ChAT-ir in GDX males and females, which are reversed by exogenous E2, P and T [ 425 – 429 ].

There are few studies examining the effects of sex and circulating hormone on cholinergic function within the striatum; however, the available data suggest that ACh signaling in the DS and NAc is sexually dimorphic. ChAT mRNA and activity vary over the course of the estrous cycle in the striatum, such that estrous females have significantly greater activity than males and females in most other stages of the cycle, which do not differ from one another [ 392 , 430 , 431 ]. Thus, when the cycle is not considered, males and females are often reported to have equivalent levels of ChAT activity in the striatum [ 432 ]. These differences are likely the result of the effects of E2 and P on ChAT gene expression, which interact to regulate ChAT mRNA abundance [ 433 ].

The density of AChE staining in the DS and NAc is not sexually dimorphic [ 434 ]; however, AChE activity in the striatum is reported to be greater in males [ 435 ] and increased in females following OVX [ 436 ]. Further muddying the waters of how these sex differences in ACh biosynthesis and degradation might impact the functional output of the striatum is the fact that ACh receptor profiles are also sexually dimorphic.

Males and females have similar total concentrations of mAChR binding sites in the striatum [ 430 ]. Overall, the affinity of mAChR is higher in cycling females rats compared to intact males, which is largely due to the increased affinity of females with high levels of endogenous E2. Exogenous E2 also increases the affinity of mAChR binding in OVX females [ 430 ]. Young women also have greater total mAChR binding in the striatum compared to post-menopausal women, which is attributed to E2, as post-menopausal women receiving E2 replacement therapy (ERT) have greater binding than their counterparts that have never had ERT [ 437 ]. Whether the sex differences in mAChR affinity reflect modifications of mAChR binding properties, or shifts in the differential expression of mAChR subtypes is unknown. Expression patterns of M1 and M1 receptor binding are different in males and females [ 392 ], which may very well translate into different patterns of synaptic integration in the striatum. Much less is known about sex differences in nAChR expression and function in the striatum. The mRNA expression of several α and β nAChR subunits in the SN and VTA appears to be similar in males and females [ 438 ].

Given the importance of striatal ACh neurotransmission in behavioral flexibility and conditioning and it interactions with DA signaling, it is not surprising that this system is implicated in the effects of drugs and the development of dependence (reviewed in [ 439 ]). However, the dynamic nature of the ACh signal (i.e., tonic versus burst/pause firing patterns) and sex differences throughout the system have made it difficult to ascertain the functional contributions of cholinergic neurotransmission within the striatum to the effects of drugs and sex differences herein.

Stress-related psychopathologies in relation to drug use disorders

As mentioned earlier, there is a high level of comorbidity between drug abuse and (often stress-related) psychiatric disorders (i.e., major depression, PTSD and anxiety disorders, which have a 2–3 times higher prevalence in women), with comorbidity being associated with more psychological and social problems and poorer outcome [ 440 – 443 ]. Interestingly this association is especially prominent in women [ 15 , 442 , 443 ], The causal relationship between substance abuse and stress-related disorders is not an unidirectional one. In adolescence psychiatric disorders appear to precede the drug abuse problems in women [ 444 , 445 ].

For depression, in men substance abuse frequently precedes depression, whereas in women depression precedes substance abuse [ 442 ]. A subpopulation of substance abusers begin using drugs primarily as self-medication, entering the spiral at the negative reinforcement segment. Cessation of drug taking brings on additional negative symptoms during withdrawal, in addition to the resurfacing of the pre-existing condition the drugs were taken to alleviate. This results in greater and more rapid escalation of drug use. It also puts subjects at greater risk of relapse, since drugs of abuse likely have not taken away the initial reasons that they started using drugs in the first place. Thus, the downward spiral is accelerated, again consistent with clinical and basic data discussed above (Figure 5 ).

The downward spiral from self-medication into addiction. The spiral depicts individuals who start using drugs primarily due to negative reinforcement mechanisms, such as seeking relief from chronic negative feelings, stress-related psychopathologies or victimization (indicated by the blue/grey shading). The drug-induced (large orange arrow) euphoria is likely attenuated in these individuals and the following post-intoxication “crash,” may temporarily exacerbate their initial dysphoria that continues unabated during drug-free periods (large grey arrows). As drug use becomes less regulated, the intervals between intoxicating events become shorter (as depicted by the narrowing of the spirals), intake increases, the positive effects become further attenuated and the dysphoria/negative affective state becomes more protracted/exacerbated. These features of addiction are the result of several interacting neurochemical changes in reward-related brain regions, including a hypodopaminergic state, characterized by reduced basal and stimulated DA concentrations (green arrows), and augmented NE (yellow arrow), CRF (pink arrow) and DYN (dark purple/blue arrow) signaling. The inhibition of other opioid systems (e.g., ENK/END/EM) (blue arrow) that contribute to positive affective state may also contribute to the dysphoria experienced by those with stress-related psychopathologies and during the development of dependence. Since many of these adaptations are already present in individuals coping with chronic stress and its associated psychopathologies even before drug use, the downward spiral may be accelerated. Women are more likely to develop stress-related psychopathologies, suggesting that a greater proportion of women may initiate drug use for self-medication, whereas a larger proportion of men may initiate drug use for their positive effects (Figure 1). Sex differences in individuals with comorbid psychopathology may also lead to different trajectories toward dependence in men and women, and in sex-specific neurochemical changes. (The magnitude of neurochemical responses is indicated by the relative sizes of the arrows, refer to text for details on sex differences).

With the extensive sex-differences in both the effects of stress and drugs of abuse, it is likely that stress-systems are involved in the higher vulnerability of females to certain aspects of substance abuse. Additionally, the coexistence of stress-related disorders and substance abuse could differentially affect the underlying neurobiological mechanisms in males and females.

Koob and Moal [ 1 ] depicted the process of addiction as a downward spiral with initially drug taking being maintained by drug-induced euphoria, which is followed by modest periods of negative affect (i.e., post-intoxication crashes) and relatively normal function in between intoxication events. Eventually, drug-induced neuroadaptations (i.e., hyperactivation of stress and anti-reward systems) leads to prolonged periods of withdrawal/dysphoria following cessation of drug taking. During this stage of abuse, negative reinforcement begins to maintain drug taking. Finally, in the end stage of addiction, drug taking is maintained both by negative reinforcement and habit formation, which contributes to the compulsive nature of drug taking (Figure 1 ).

Stress-related disorders, as post-traumatic stress disorder (PTSD) and depression, lead to neurobiological changes in brain reward systems, which likely has consequences for both positive and negative effects of drugs of abuse and could thus affect the transitioning from use to abuse. For example, depressed subjects show a hypersensitive response to the rewarding effects of AMPH [ 446 ], which is associated with a relative decrease in brain activity, in a.o. the PFC and caudate putamen [ 447 ], indicative of an hypodopaminergic state. It is to our knowledge unknown if the response to psychostimulants is changed in subjects with PTSD, or if there are sex differences in the acute effect of abused drugs in people suffering from major depression or PTSD. However for subjective effects of AMPH an opposite response has also been observed in a nonclinical sample, with subjects that reported more severe life stress had an attenuated pleasant response to AMPH. Also higher stress levels were associated with a blunted striatal DA response [ 448 ]. Unfortunately no sex differences were reported.

Both major depression and PTSD, affect HPA-axis activity albeit in different ways, in general PTSD is associated with a hyperactive central CRF and NE system and blunted HPA-axis activity, whereas with major depression it varies with the subtype of depression [ 449 ] (for review see [ 450 ]. Addiction has a high comorbidity with both, but with (possibly sex-specific) differences in underlying neurobiological dysfunctions, the consequences of drugs of abuse in the brain are likely (at least partly) dependent on the comorbid disorder. Little data is available on sex-differences. Brain maturation is differently affected in boys and girls suffering from maltreatment-related pediatric PTSD, with boys showing more adverse effect than girls [ 451 ]. Also women with PTSD show and enhanced startle response, a measure for non-specific anxiety, compared to men [ 452 ], which indicate sex differences limbic brain systems in PTSD.

As described earlier stress exposure is used as an animal model for depression and PTSD, and especially depression could be viewed as being in a dysphoric state. Although the distinction between different human stress-related disorders is hard to model specifically in animal stress models. And chronic of severe stress likely induces changes mimicking aspects of both depression and PTSD in animals.

Female rats exposed to isolation stress during puberty were shown to be more sensitive to the AMPH-induced locomotor activity compared to males [ 453 ]. Chronically stress rodents show an attenuated basal DA [ 454 – 456 ], which is though to underlie symptoms of anhedonia. These data appear to correspond with the findings in depressed patients of increased subjective effects and a reduced response in the brain reward system [ 446 , 447 ].

Repeated social defeat stress in rats affects the locomotor response to stimulants, which could be related to the positive subjective effects, cocaine self-administration. Defeated animals show a faster acquisition and a higher motivation to self-administer cocaine [ 457 – 459 ]. Also social stress results in escalation of cocaine, but not heroin, intake [ 460 ]. In addition, chronic social stress affects the DA response to cocaine in males, although the direction of the change depends on whether the stress was continuous or intermittent [ 461 ]. In females drug-induced increases in DA levels are attenuated after chronic stress [ 455 ].

Summarizing, the link between drug abuse and stress-related psychiatric disorders is well known. Sex differences in prevalence of those disorders is also well established. There is very limited information, however, on how this affects the pattern of drug use and if the underlying neurobiology is different dependent on the comorbid psychopathology.

Review and conclusions

Our theoretical model presented in Figure 5 is based on the evidence reviewed above demonstrating that there are sex differences in the clinical presentation of addiction and in the neural substrates contributing to addiction. The model highlights three concepts that are essential to understanding the neurobiology of addiction: 1) addiction affects many different brain regions; 2) addiction manifests as a constellation of clinical features that collectively result in the maladaptive behavior exhibited by addicts; and 3) the presence of psychopathologies prior to drug use impacts the rate of deterioration into addiction. The magnitude of involvement of individual systems is hypothesized to differ between males and females, as described in Figure 2 and discussed above. Considered together, it is clear that effective treatments for addiction will require sex/gender-specific combinations of drugs targeting the multiple systems that are dysregulated in the addicted brain, and additionally consider comorbid psychopathologies.

Females show enhanced engagement of the DA system during initial drug exposure. As discussed above there is initially greater release of DA and an enhanced sensitivity to inhibition of uptake by stimulants in females. Chronic drug use results in a hypodopaminergic state within the striatum of both sexes, which has a greater impact in females due the enhanced sensitivity to DA. Drug use and exposure to drug-related cues are associated with increases in DA release, however, reduced DA levels between periods of drug use result in a state of dysphoria and anhedonia in which interest in natural rewards and previously preferred activities is reduced. This period is associated with enhanced drug-seeking behavior as the addict seeks to reduce craving and alleviate the dysphoria. In fact, drug use may be seen as a form of self-medication to deal with the abnormally low DA levels. Chronic drug use is also associated with enhanced engagement of NE signaling within the CeA/BST and NAc, which contributes to the negative affective state, dysphoria, anxiety and irritability associated with withdrawal. In females this negative state is exacerbated due to greater noradrenergic and CRF activity.

The sexually dimorphic behavioral patterns of drug abuse are hypothesized to be due to sex differences in the neural systems mediating acquisition and escalation of drug taking behavior. The areas of the brain involved in the neural basis for motivation begin conceptually with the ascending DA systems that project from the SN/VTA to the DS, NAc, CeA/BST, Fcx. These DA projections are involved in the initiation of drug taking and according to some models the progression from use to compulsive drug use [ 462 ].

Comorbidity between drug abuse and stress-related psychiatric disorders is associated with more psychological and social problems and poorer outcome, especially in women. Brain circuitry affected by these disorders overlaps with circuitry involved the effects of drugs of abuse, which could exacerbate the effects of drugs of abuse and lead to higher risk of transitioning from drug use to dependence and a faster escalation of drug use.

Implications for treatment

There are very few effective treatments for psychostimulant addiction, and as such frequent relapses are a hallmark of the addiction cycle [ 463 – 465 ]. Naltrexone and disulfiram have been shown to reduce cocaine intake in men, but these treatments are not effective in women [ 466 , 467 ]. It is therefore important to test possible pharmacological interventions in both males and females. Mitigating the negative effects associated with addiction, like dysphoria, anxiety and irritability will likely reduce the frequency of drug taking and the chance of relapse. The stress-axes and κ-opioid/DYN signaling are involved in mediating these withdrawal symptoms, and pharmacological interventions targeting these systems could prove to be therapeutically interesting. With women being more sensitive to stress-induced craving, and sex-differences being present in the stress system, noradrenergic projections, and in κ-opioid/DYN signaling, it is conceivable that sex/gender will affect treatment outcome of pharmacological interventions targeting these systems.

The βAR antagonist propranolol has modest effects in promoting treatment retention and cocaine abstinence, which are mostly observed in individuals with more severe withdrawal symptoms [ 468 , 469 ]. Thus, noradrenergic antagonism on its own may only be effective at targeting the negative affective state ostensibly mediated by increased NE signaling in the CeA/BST.

There are even fewer studies examining the efficacy of cholinergic manipulations on clinical outcomes of stimulant addiction [ 470 ]. In general, AChE inhibitors have modest effects that are most pronounced on the subjective effects of stimulants, with little effect on actual drug use [ 471 – 473 ]. The relatively modest (or absent) effects of AChE inhibitors might relate to the fact that they chronically elevate ACh concentrations, which can lead to desensitization and loss of nicotinic receptors or promote the non-selective activation of both M1- and M2-like receptors.

The effects of more selective cholinergic manipulations on drug use in humans have also been examined. The administration of nicotine attenuated the subjective effects of intranasal (but not intravenous) cocaine, and increased the latency for detecting the effects of cocaine and euphoria [ 474 , 475 ]. Pre-treatment with mecamylamine, a nicotinic antagonist, was also shown to reduce cue-induce craving in cocaine addicts [ 417 ], whereas varenicline, a partial α4β2 agonist and full α7 agonist, tended to promote abstinence and reduced the rewarding value of cocaine [ 476 ]. The effects of nicotinic agonists and antagonists may result in similar effects through tonic activation and desensitization of nicotinic, which could explain why both treatments reduce the sensitivity to drugs and their cues. Preclinical research suggests that muscarinic interventions might also be beneficial [ 396 , 416 , 470 , 477 ]; however, we are not aware of any clinical data on the effects of selective muscarinic treatments on stimulant addiction. In the most of the studies examining cholinergic manipulations, the majority (or in some cases all) of the participants were men; therefore, it is also difficult to say whether men and women will show similar effects.

Opiate addiction is on the rise again, especially in relation to the abuse of prescription drugs. Unintentional overdose deaths involving opioid pain relievers have increased dramatically since 1999, and by 2007, outnumbered those involving heroin and cocaine [ 478 ]. Although more men than women use heroin, young women show a higher rate of dependence to non-medically used psychotherapeutics, which include pain relievers, sedatives, stimulants, and tranquilizers. The reason for using appears to be different between men and women, with men going for the high and rush, whereas women use it more as a form of self-medication [ 23 ]. This could reflect a difference in underlying neurobiological mechanisms on which the drugs act and have implications for possible pharmacological interventions. Studies using self-administration of opioids in both males and females are few, and if chronic exposure to self-administered opioids have differential effects on the brain of males and females as would be predicted from the data presented in this review, risk factors and treatment options will also be sexually dimorphic. With discreet behavioral profiles and neurobiological substrates of cocaine and heroin addiction [ 479 ], it cannot be expected that sex-specific findings for cocaine can be extrapolated to opioids.

Concluding remarks

Currently, preclinical research is focused primarily on examining the acute effects of stimulants and other abused drugs and how they are influenced by pharmacological interventions. While these acute responses to drugs of abuse can provide valuable information about possible mechanisms of action, they are less informative in regards to developing new pharmacotherapies for addiction. This is because chronic drug abuse induces major changes in the brain that are often different from those occurring in response to passive drug exposure. Thus, in order for pharmacological interventions to be effective, they must target what is “wrong” in the addicted brain, which will likely not respond similar to a healthy brain exposed to acute drugs of abuse. It is therefore important to investigate possible pharmacological interventions in animal models that better reflect the suite of behavioral (and ostensibly neurochemical) changes that occur following chronic drug use, especially as they relate to addiction-like criteria.

Additionally, little is known about the neurobiological consequences of chronic exposure to drugs of abuse in females. While data collected from male subjects provide important information of how the male brain copes with repeated stimulation of the reward system, it is unlikely that the female brain responds in the same way. With drugs of abuse having sex-specific effects on behavior and the brain, it is vital to test effectiveness of new treatments and underlying neurobiological mechanisms in both male and female subjects.

1 The Harrison Tax Act is the reason the Dept. of the Treasury was responsible for enforcement of drug laws until the 1969 Dangerous Substances Act was enacted.

Abbreviations

acetylcholine

acetylcholine-esterase

adrenocorticotropic hormone

amphetamine

androgen receptor

bed nucleus of the stria terminalis

central nucleus of the amygdala

choline Acetyltransferase

cortisol/corticosterone

conditioned place preference

corticotropin releasing factor

D2,D5, dopamine receptor 1, 2 or 5

dopamine transporter

dorsal striatum

endomorphin

estrogen receptor

frontal cortex

gamma-aminobutyric acid

hypothalamic-pituitary-adrenal-axis

locus coeruleus

medium spiny neuron

muscarinic acetylcholine receptor

nucleus accumbens

nicotinic acetylcholine receptor

norepinephrine

norepinephrine transporter

nucleus of the solitary tract

opioid receptor

ovariectomy/ovariectomized

progesterone

post traumatic stress disorder

substantia nigra

testosterone

tyrosine hydroxylase

ventral tegmental area.

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Financial support for this research was contributed by NIH grant R01-DA012677 to JBB. AP was supported by NIH DA007268 (T32).

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Becker, J.B., Perry, A.N. & Westenbroek, C. Sex differences in the neural mechanisms mediating addiction: a new synthesis and hypothesis. Biol Sex Differ 3 , 14 (2012). https://doi.org/10.1186/2042-6410-3-14

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Rob lowe says threesome sex tape leak ‘changed my life,’ led to him getting sober.

Rob Lowe credits the fallout from his notorious sex tape being leaked with helping him get sober.

The “St. Elmo’s Fire” actor, 60, said in a new interview with People that the 1988 scandal, while humiliating for him at the time, was actually a major reason he beat his struggles with addiction.

“[The fallout] definitely changed my life at the time, and, in hindsight, I realized it was another step that led me to recovery and re-evaluating my life,” he said.

“But the thing that really changed me was not being able to show up for my family and myself,” Lowe added.

The former Brat Pack member was just 24 years old when he was caught in a rendezvous with two women , one age 22 and the other just 16.

Lowe shot to fame in the 1980s and began drinking as a teen, entering into a life of hard partying to cope with his success at the time that the sex tape was leaked.

During an interview on SiriusXM’s “The Jess Cagle Show” in 2019, Lowe quipped that he “invented” the sex tape, before admitting that that scandal helped him get sober.

“It’s one of the reasons why I got sober. I woke up one day and I was like, ‘What am I doing with my life?’ ” he said. “I’m 29 years in and like people talk, but it’s the best thing that ever happened to me. Honestly, I do because it got me sober, sober got me married.”

“I’ve been married 29 years and I have two great sons,” he added. “I don’t think any of that happens without going through that scandal.”

Last year, Lowe’s son John Owen Lowe , 29, revealed he was in high school when he learned about his dad’s sex tape.

“I was in eighth grade or freshman year of high school, and some kid said, ‘You know, your dad has a sex tape online,’” John told Men’s Health . “I was like, ‘What?’”

Rob Lowe, Demi Moore in "About Last Night" in 1986

He said the “Parks and Recreation” star and his mother, Sheryl Berkoff , never spoke to him and his older brother, Matthew, 31, about the explicit recording.

“I don’t think most parents ever have that moment where they sit the kids down and go, ‘OK, we’ve got to tell you something.’ A kid just figures it out,” said John. “There weren’t milestone markers, like, ‘OK, he’s 16 now, time for them to learn about this part of our life!’”

In 1990, Lowe quit drinking and sought help from a rehab program . He’s been sober ever since.

“Getting sober was an incremental decision,” he said in his People interview. “It’s baby steps until you’re ready. You can’t do it until you’re really ready.”

Rob Lowe at the DuJour August 2024 Issue Cover Party

Lowe added, “I didn’t have any doubts [and] I wasn’t like, well, maybe I’ll be sober for a little bit. I always tell people: You can’t get sober … I don’t care if it’s fentanyl, booze, drugs, coke, pot, gambling, overeating, sex addiction, whatever, you cannot stop for your job, your wife, your family, your parole officer, because you screwed something up.”

The “West Wing” alum said that going to rehab was “relieving” and “scary,” but when he was there, he “learned the tools to change your life if you have the self-honesty to do it.”

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The Benefits of Ozempic Are Multiplying

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You’ve heard the dramatic weight loss stories. Semaglutide, the active ingredient in Ozempic and Wegovy , can help people lose 15 percent of their body weight. Tirzepatide, sold under the brand names Mounjaro and Zepbound , may be even more effective at shedding pounds.

Known as GLP-1 agonists, these drugs were originally developed to help control diabetes. But there’s increasing evidence that they have other health benefits, beyond controlling weight. They seem to boost heart health, protect the kidneys, improve sleep apnea , and lower the risk of certain obesity-related cancers . Recent studies have also hinted at their potential to treat addiction and even slow the cognitive decline that comes with dementia. As researchers test these drugs for various conditions, they’re trying to untangle the mysteries behind how exactly they’re working in the body—and they have a few theories.

“Many of us in the medical community are really beginning to think about these drugs as health promotion drugs, not just weight loss drugs or even anti-obesity drugs,” says Harlan Krumholz, a cardiologist and professor at Yale University School of Medicine.

In March, Novo Nordisk’s Wegovy became the first weight loss medication to also gain approval to help prevent serious heart problems in people with cardiovascular disease. In an international trial of more than 17,600 people with excess weight, weekly injections of Wegovy significantly reduced the risk of a major cardiac event . Researchers followed participants for an average of three years and found that those who took Wegovy were 20 percent less likely to die of a heart attack, stroke, or other cardiovascular cause.

Eli Lilly, which makes tirzepatide, is also looking to expand Zepbound’s uses. The company announced this month that its weight-loss drug improved symptoms in heart failure patients with obesity and led to a 38 percent reduction in hospitalizations.

One in every four deaths each year in the United States is due to heart disease, and obesity is increasingly a factor . Excess weight can cause high blood pressure and cholesterol, which increases the risk of heart attack and stroke. Weight gain can also affect how the heart muscle functions, increasing the risk of failure. It’s perhaps no wonder then that a drug that helps people lose weight would also improve heart health. But there are reasons to think there are other factors at play beyond weight loss.

“When we first saw the results, we wondered, is this simply about weight loss?” Krumholz says. “But what we’re seeing is that having more weight loss doesn't necessarily translate into more benefit.”

In the trial of people with heart disease, Wegovy lowered blood pressure, cholesterol levels, heart rate, and heart inflammation before participants reached their maximum weight loss. What’s more, the drug seemed to reduce major cardiac events regardless of how much weight they lost . The same was true for heart failure patients. This all suggests to Krumholz that the drug is, at least in part, working on the cardiovascular system in some other way. “This is the big question,” he says. “What is the exact mechanism of benefit?”

Semaglutide and tirzepatide work by mimicking the action of GLP-1, a hormone found naturally in the body. These drugs act on GLP-1 receptors in the pancreas to trigger the release of insulin after eating, which helps control blood sugar levels in people with diabetes. They also bind to GLP-1 receptors in the brain to make people feel full, leading them to eat less.

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Scientists are still trying to understand the other knock-on effects of these drugs, including the cardiovascular benefits. One explanation is that GLP-1 receptors also exist on cells in the heart, blood vessels, liver, and kidney, so these drugs may act directly on these organs. “It turns out that these receptors are present in many parts of the body,” says Katherine Tuttle, a clinical professor of nephrology at the University of Washington School of Medicine.

A recent trial led by Tuttle was stopped early due to overwhelming evidence that semaglutide has protective effects on the kidney. The study included more than 3,500 people with both type 2 diabetes and kidney disease. About half of the participants took a weekly injection of semaglutide while the other half got a placebo shot. After an average of three and a half years, the semaglutide group had a 24 percent lower likelihood of having a major kidney disease event—such as needing dialysis or a kidney transplant.

Clinical trials aren’t usually designed to determine the mechanism of a drug—and in fact, the mechanisms of many drugs on the market aren’t entirely known. But Tuttle has her own theory for how semaglutide is protecting the kidney: by shutting down inflammation.

GLP-1 drugs may even calm inflammation in the brain, raising hope that they could be used to treat conditions like dementia and Parkinson’s disease. Inflammation is thought to play a role in the development of both conditions.

In a UK trial of 200 people with mild Alzheimer’s disease, an older GLP-1 drug called liraglutide appeared to slow shrinking of the parts of the brain that control memory, learning, language, and decisionmaking by as much as 50 percent. Those who received weekly injections of liraglutide over 52 weeks also had an 18 percent slower decline in cognitive function after a year compared to those who got the placebo. Obesity is a known risk factor for developing Alzheimer’s disease, but the study didn’t specifically include people with obesity, which suggests that the drug is helping through another means.

The authors, who presented the findings last month at the Alzheimer’s Association annual conference, think liraglutide could be working in a few different ways—including reducing inflammation in the brain and lowering insulin resistance.

Heather Snyder, vice president of medical and scientific relations at the Alzheimer’s Association, says the results are exciting, although larger trials will be needed to confirm this protective effect. “This is really the first study where we’ve seen a hint of this benefit for individuals,” she says.

And the neuroprotective effects may extend to Parkinson’s disease as well. An older diabetes drug in the GLP-1 family, lixisenatide, seemed to slow the progression of Parkinson’s symptoms in a small study of 156 patients in France. In results published in April , participants with early-stage Parkinson’s who took the drug for a year saw no worsening of motor symptoms such as tremors, balance problems, slowness, and stiffness. Those who received a placebo, meanwhile, experienced a decline over the same period.

Because GLP-1 drugs interact with the brain and seem to curb food cravings, scientists wonder if these medications could also curb cravings for addictive substances. Parts of the brain involved in eating behaviors are also involved in the use of alcohol and drugs. In mice, semaglutide has been shown to reduce alcohol consumption and binge-like drinking , and some people who have taken semaglutide and other GLP-1 drugs have self-reported less drinking and smoking.

In 2019, researchers at Penn State wanted to see if this class of drugs could help reduce cravings in people with opioid use disorder. In experiments with rats, they showed that GLP-1 drugs could reduce fentanyl-seeking behavior and relapse to heroin. The group launched a pilot study of 20 participants who were living at a residential treatment facility. Half were given the GLP-1 drug liraglutide, and the other half received a placebo. Measuring cravings can be tricky, so researchers used a smartphone app that pinged people four times a day to ask about their craving as well as their mood and stress levels.

When the three-week study ended, researchers found that those who received the GLP-1 drug reported a 40 percent reduction in opioid craving compared to those who got the placebo. The study didn’t follow participants after they left the residential facility, so it’s not known whether the drug actually curbed their opioid use. That, of course, is the important outcome, since many people who initially recover from addiction experience a relapse.

Patricia Grigson, a professor of neural and behavioral sciences at Penn State College of Medicine who led the study, says GLP-1 drugs seem to block the signal in the brain that gets released after eating or taking an addictive substance. “It would appear that they're just knocking down that reward signal,” she says. Grigson presented the findings at the American Association for the Advancement of Science conference earlier this year. Her group will test semaglutide next in 200 people getting treatment for opioid addiction, and they plan to start recruiting participants for that study this fall.

With so many people turning to GLP-1 drugs to lose weight, their other health benefits may soon become clearer—and so could the answers about how exactly they’re working. Grigson says newer drugs like tirzepatide, as well as ones still in development , may work even better than previous GLP-1 medications. “If they look safe, they need to be tested,” she says. “And the sooner, the better.”

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Sexual Addiction Disorder— A Review With Recent Updates
Important attributes that distinguish sexual addiction disorder from other patterns of sexual behavior are (a) failure to control sexual behavior and (b) the sexual behavior has significant harmful consequences and (c) continues despite these consequences. 3 Sexual addiction disorder is a serious clinical problem with damaging consequences if ...
(PDF) Sexual Addiction Theory, causes and therapy
PDF | On Nov 1, 2012, Francesca Tripodi and others published Sexual Addiction Theory, causes and therapy | Find, read and cite all the research you need on ResearchGate
PDF SEX ADDICTION: IN THE EYE OF THE BEHOLDER?
2 Thesis Abstract Introduction: 'Sex addiction' appears to have been largely accepted within clinical fields and popular culture. However, despite its 30 year history, the concept remains ill-defined and lacking in empirical data.
Sexual Addiction, Hypersexual Behavior and Relative Psychological
Sexual Addiction is a disorder characterized by intrusive and obsessive sexual thoughts and fantasies, associated with loss of control over sexual behavior that causes negative consequences at work, emotional, and social levels [7,9]. Defined sex addiction as the consequence of a hyper-sexuality of the subject, understood as an above-average ...
Sexual addiction 25 years on: A systematic and methodological review of
1. Introduction. A little more than two decades ago, Gold and Heffner (1998) published a pivotal paper in Clinical Psychological Review about the nature of "sexual addiction." At the time, the concept—popularized by Patrick Carnes fifteen years earlier (Carnes, 1983)—was gaining increasing attention in clinical settings and in popular media.. However, after thoroughly reviewing the ...
Sexual addiction 25 years on: A systematic and methodological ...
In 1998, Gold and Heffner authored a landmark review in Clinical Psychology Review on the topic of sexual addiction that concluded that sexual addiction, though increasingly popular in mental health settings, was largely based on speculation, with virtually no empirical basis. In the more than two d …
Sexual addiction 25 years on: A systematic and ...
Introduction. A little more than two decades ago, Gold and Heffner (1998) published a pivotal paper in Clinical Psychological Review about the nature of "sexual addiction." At the time, the concept—popularized by Patrick Carnes fifteen years earlier (Carnes, 1983)—was gaining increasing attention in clinical settings and in popular media.
Psychosocial intervention for sexual addiction
The Sexual compulsivity scale is most commonly used for gauging the presence of sexual addiction. It includes both the key features of addiction (impaired control and harmful consequences). It is a 10 item scale which scores from 1-4. The cut off value is 24.
Sex Addiction
'Sex addiction' was a grassroots term that seemed to capture the experience of those struggling with 'out-of-control' sexual behaviour, and emphasized commonalities between AA members' experience with sex and their experience with alcohol. Although the term was controversial, by the late 1980s, extensive media coverage popularized the ...
Sexual addiction 25 years on: A systematic and ...
Request PDF | Sexual addiction 25 years on: A systematic and methodological review of empirical literature and an agenda for future research | In 1998, Gold and Heffner authored a landmark review ...
Sex addiction: therapist perspectives
ABSTRACT. Sexual addiction may be defined as sexual behaviour that is "compulsive and yet continues despite adverse consequences". Knowledge and understanding of sexual addiction has been impaired by the use of multiple labels, definitions, and assessment procedures, hence the present study investigated therapist perspectives and experiences of assessing and treating the condition.
Debating the Conceptualization of Sex as an Addictive Disorder
As with other behavioral addictions, sexual addiction is conceptualized as being synonymous with substance use disorders. The notion that sexual behavior could be potentially addictive was first introduced by Orford [], but it has become most widely attributed to Patrick Carnes' [] book: Out of the Shadows: Understanding Sexual Addiction.Carnes described sexual addiction as representing a ...
Sexual addiction: insights from psychoanalysis and functional
Sexual motivation is a fundamental behavior in human. For a long time, this behavior has been somehow ignored from psychological and neuroscientific research. In this article - reflecting the collaboration of a clinical psychologist and a neuroscientist - we show that in the current period, sexual affiliation is one of the most promising ...
PDF Sex Addiction: Therapist Perspectives
Sexual addiction may be defined as sexual behaviour that is "compulsive and yet continues despite adverse consequences" (Carnes & Adams, 2013, p5). Knowledge and understanding of sexual addiction has been impaired by the use of multiple labels, definitions, and assessment procedures, hence the present study investigated therapist
PDF Purnell Thesis 2019-03-11d
Sex addiction counselling inevitably involves ethical tensions that affect ethical practice (Griffin-Shelley, 2009; Herring, 2001; Schneider & Levinson, 2006). As a result, there is a need for research that specifically addresses ethical tensions in sex addiction counselling and explores how counsellors experience these tensions in their work.
Sexual addiction: insights from psychoanalysis and functional neuroimaging
3. a phase of sexual activity, which leads to a tempor-ary and provisory relief; and 4. a phase of despair with a sentiment of the incapacity to control one's own behavior. Like other forms of dependency, sexual addiction builds up through a process in which several stages can be distinguished: experimentation, occasional (festive) use,
Sex Addiction: A Literary and Yogic Perspective
Sex Addiction: A Literary and Yogic Perspective. Adrienne Hope Hite. Follow this and additional works at: https://digitalcommons.lmu.edu/etd. Part of the Mental and Social Health Commons. This Thesis is brought to you for free and open access by Digital Commons @ Loyola Marymount University and Loyola Law School.
Sex Addiction: An Overview
To further investigate and validate the diagnosis, researchers began to develop testing instruments. Carnes accumulated data on more than 1,600 cases (1991); developed several self-report screening measures such as a 25-item Sexual Addiction Screening Test (SAST); and developed a brief screening test (Carnes et al., 2011) that was similar to the CAGE, a 4-item assessment for alcohol dependency ...
Impacts of Sexual Addiction on Intimate Female Partners—The State of
ABSTRACT. There has been a surge of research articles in the last two decades about sexual addiction (SA) and compulsive sexual behavior (CSB). In the literature, SA/CSB is mostly presented as being comparable to other behavioral addictions and similarly involves a problematic consumption model: loss of control, psycho-social impairments, and risky sexual activities.
Understanding the Roots of Sexual Addiction
The beliefs the addict often holds deep within their psyche are: personal beliefs, such as, "I am flawed and unworthy of love;" relational beliefs, such as, "If people knew me they would not love me;" beliefs about needs, such as, "My needs will never be met if I have to rely on others;" and sexual beliefs, such as, "Sex is my ...
Sex differences in the neural mechanisms mediating addiction: a new
It is the thesis of this review that sex differences exist along every aspect of the spiral pathway towards addiction. In addition, we propose the existence of a second "steeper" spiral, for which initiation of drug taking occurs to alleviate self-perceived symptoms of (stress-related) psychiatric disorders.
PDF Harvard University
Harvard University
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Rob Lowe credits the fallout from his notorious sex tape being leaked with helping him get sober. The "St. Elmo's Fire" actor, 60, said in a new interview with People that the 1988 scandal ...
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A spokesperson for Republican vice presidential nominee JD Vance cited the Minnesota law to back Vance's claim Aug. 7, 2024, in Eau Claire, Wisconsin, that Walz supports removing custody from parents who "don't want to consent to sex changes." This fact brief is responsive to conversations such as this one. Sources
Love addiction, sexual addiction and perceived social support
They required Italy; 3Integrated Center of Clin- ical Sexology â€œIl Ponteâ€ , Integrated Center of Clinical Sexology â€œIl Ponteâ€ , Florence, ItalyJ Sex Med 2022;19:S37âˆ'S48Objectives: Our study aimed to examine the relationship between love addiction and sex addiction and the degree in which they are influenced by ...
Sexual Assault in US. Army
Sexual Assault in US. Army. Subject Librarians; Duke. Databases Broadly related to this Topic; Archives and Digital Collections; Secondary Materials- Books; Secondary Materials- Articles; Topic: Page Act; Topic: Credit Lending and the Rise of Investment Banking; Topic: Child Welfare Legislation; Topic: Reagan to 9/11: Impacts on American Muslim ...
The Relationship Between Love Addiction and Sex Addiction and the
Our study examined the relationship between love addiction and sex addiction and the degree to which they are influenced by perceived social support. The study involved a clinical and a control group of 497 and 409 participants respectively. The clinical group showed significantly higher levels of love addiction and sex addiction, as well as ...
Court hears of killer's troubled upbringing, sex worker addiction
The 21-year-old man convicted of raping and killing six Zimbabwean sex workers in Johannesburg two years ago admitted that he engaged the services of sex workers when he was only 15, the Gauteng High Court, sitting in Palm Ridge, has heard. ... sex worker addiction Ntwaagae Seleka Comments Gift article. Bookmark. Share your Subscriber Article ...
The Benefits of Ozempic Are Multiplying
There's mounting evidence that GLP-1 drugs have health benefits beyond diabetes and weight loss, for conditions ranging from addiction to Parkinson's—and scientists are evolving theories of why.
Did Eric Hovde say single parenthood leads to poverty and drug addiction?
A Baldwin ad excerpted Hovde's comments and claimed he "thinks if you have a single mom, you're going to be poor or a drug addict." Hovde's campaign said that's not what Hovde thinks and that he was alluding to federal data showing single-parent households linked to poverty and drug abuse.

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Sexual addiction: insights from psychoanalysis and functional neuroimaging

Harold Mouras

The concept of addictive sexuality

Elements of psychopathology

Time immobilized by the repetition compulsion

How to live without belief?

Relationship zapping and the anonymity of encounters

The space of the backrooms

Personality traits, defense mechanisms

The love/sex split

Idealization, omnipotence, and devalorization

Anaclitic anxieties and their avoidance

Comorbid disorders and risk taking

Risk taking (barebacking, HIV, STD, etc.)

Masked depression

Research in neurobiology

Recent advances from neuroimaging studies

Two emerging fields within cognitive neuroscience: affective and social neurosciences

Sexual affiliation: a functional context between affective and social neurosciences

Contemporary data on healthy human male sexual function

Exploratory data on CSB

Therapeutic

Behavioral individual or group SAA therapies

Issues of psychodynamic therapies

Pharmacological aspects

Conflict of interest and funding

November 17, 2017

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