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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.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 [], 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.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.A larger proportion of men compared to women may initiate drug use for their positive effects.

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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.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.].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).

It is the thesis of this review that sex differences exist along every aspect of the spiral pathway towards addiction.

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