Consideration of sex and gender differences in addiction medication response

Abstract

Substance use continues to contribute to significant morbidity and mortality in the United States, for both women and men, more so than any other preventable health condition. To reduce the public health burden attributable to substances, the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism have identified that medication development for substance use disorder is a high priority research area. Furthermore, both Institutes have stated that research on sex and gender differences in substance use medication development is a critical area. The purpose of the current narrative review is to highlight how sex and gender have been considered (or not) in medication trials for substance use disorders to clarify and summarize what is known regarding sex and gender differences in efficacy and to provide direction to the field to advance medication development that is consistent with current NIH ‘sex as a biological variable’ (SABV) policy. To that end, we reviewed major classes of abused substances (nicotine, alcohol, cocaine, cannabis, opioids) demonstrating that, sex and gender have not been well-considered in addiction medication development research. However, when adequate data on sex and gender differences have been evaluated (i.e., in tobacco cessation), clinically significant differences in response have been identified between women and men. Across the other drugs of abuse reviewed, data also suggest sex and gender may be predictive of outcome for some agents, although the relatively low representation of women in clinical research samples limits making definitive conclusions. We recommend the incorporation of sex and gender into clinical care guidelines and improved access to publicly available sex-stratified data from medication development investigations.

Trends in Alcohol-Related Deaths by Sex in the US, 1999-2020

“…Given the rates of alcohol-related mortality, it is important to acknowledge the limited knowledge of how current pharmacologic treatments for AUD specifically affect women. As emphasized by McKee and McRae-Clark, the development of medications for AUD has often overlooked potential sex and gender differences. The US Food and Drug Administration–approved medications for AUD, such as disulfiram, naltrexone, and acamprosate, have been studied primarily in men, leaving a knowledge gap regarding their association with mortality outcomes in women .…”

“…As emphasized by McKee and McRae-Clark, the development of medications for AUD has often overlooked potential sex and gender differences. The US Food and Drug Administration–approved medications for AUD, such as disulfiram, naltrexone, and acamprosate, have been studied primarily in men, leaving a knowledge gap regarding their association with mortality outcomes in women . Although these medications have shown potential in improving health outcomes, their effectiveness in reducing alcohol-related mortality remains uncertain, particularly for women .…”

“…The US Food and Drug Administration–approved medications for AUD, such as disulfiram, naltrexone, and acamprosate, have been studied primarily in men, leaving a knowledge gap regarding their association with mortality outcomes in women . Although these medications have shown potential in improving health outcomes, their effectiveness in reducing alcohol-related mortality remains uncertain, particularly for women . For example, although naltrexone has demonstrated efficacy in reducing drinking and cravings, women may experience more adverse events, leading to higher rates of treatment discontinuation .…”

Correction to: Consideration of sex and gender differences in addiction medication response

“…Following publication of the original article [ 1 ], the authors reported a typo in the first sentence of the "Abstract" and the "Introduction". The first sentences of both should read as follows: “Substance use continues to contribute to significant morbidity and mortality in the United States, for both women and men, more so than any other preventable health condition.” …”

Estrous cycle and hormone regulation of stress-induced reinstatement of reward seeking in female mice

“…Alcohol use disorder (AUD) is a devastating neuropsychiatric illness, characterized by a high propensity to relapse even after extended abstinence. It has become increasingly evident that existing pharmacotherapies are not equally effective in men and women [ 1 – 3 ]. Among individuals that engage in heavy drinking, women exhibit greater alcohol craving in response to stress than men [ 4 ] which places them at elevated risk of stress-induced relapse.…”