​Naltrexone may be a wonder drug but getting patients to take it is a challenge.


  • Naltrexone, like its cousin naloxone (Narcan), is a wonder drug but getting patients to take it is not easy.
  • Lack of treatment adherence may be genetic, but women and men also respond differently
  • Alcohol (AUD) and opioid use disorders (OUD) are two diagnoses, but the same treatment suggests commonalities.

Excess drinking and alcohol use disorder (AUD) is common, not easily diagnosed, and often undertreated, with less than 15% of individuals with a lifetime diagnosis receiving any treatment. While medication-assisted treatments (MATs) have been the major therapeutic approach for opioid use disorders, alcohol use disorders have gone mostly untreated. Yet alcohol misuse is believed to be responsible for more than 140,000 deaths annually in the United States. In addition, nearly 1 in 6 Americans reportedly binge drink, and binge drinkers may be male or female.

Benjamin Rush, father of modern American psychiatry and a signer of the Declaration of Independence, published his landmark “Inquiry Into the Effects of Ardent Spirits Upon the Human Body and Mind” in 1785. Dr. Rush, whose interest in mental illness included alcohol misuse, described it as a disease: “The use of strong drink is at first the effect of free agency. From habit, it takes place from necessity.” Rush had experience observing alcohol problems because, during the revolutionary period, Americans had an average annual consumption of 5.8 gallons of absolute alcohol per adult. Rush learned early in his career it was not logical to blame patients or their morals when treating someone with an alcohol problem.

Gender Matters

In the Rush tradition, researchers like Rajita Sinha, Foundations Fund Professor of Psychiatry and Director, Yale Interdisciplinary Stress Center, also don’t blame patients for failing to respond to treatments and instead have searched for means to make treatment more successful. Recently, Sinha has turned the addiction treatment field upside down by publishing data showing that gender matters in alcohol effects on the brain and craving and also appears to determine AUD medication treatment responses.

Her research on polysubstance use considers differences between women and men. For example, for women, higher rates of stress and trauma are linked to an increased risk of AUD compared with men. Women report higher cravings than men in response to acute stress. In addition, women generally are more likely to report chronic pain relative to men and have higher rates of anxiety and mood disorders, particularly when they already have issues with alcohol use or substance use disorders.


The three medications approved in the United States to treat AUD—disulfiram, naltrexone (oral and long-acting injectable formulations), and acamprosate—are under-prescribed. Nalmefene, an opioid antagonist used to treat opioid overdoses, is approved and prescribed for AUD in Europe. In addition, two off-label medications not approved for treating AUD in the USA, topiramate and gabapentin, are prescribed by some physicians. As mentioned in my post on ibogaine and also psilocybin, psychedelics are promising possible future additions to the treatment of AUD.

Of treatments to prevent relapse to AUD and reduce harm from alcohol, the most compelling data is for long-acting injectable naltrexone. Many studies have demonstrated the effectiveness of injectable naltrexone in reducing alcohol consumption and promoting recovery. In addition, oral naltrexone may be used to reduce harm from binge drinking.

Binge drinking refers to four or more drinks within about three hours in females or five or more drinks over the same period in males. However, among binge drinkers, prescribing a single pill of naltrexone when the patient actively craves alcohol or before events when they thought they might be at risk for heavy drinking, such as a work holiday party, led to less binge drinking and less drinking overall in a 90-day study. For a binge drinker, many harm reduction strategy experts suggest bringing the drug to parties and having a pill or two in the pocket.

It’s important to note that success rates with coping with AUD are not uniform, and treatment outcomes vary widely. It also appears that active participation in a 12-step or similar program, treatment of co-morbidities, and personalized pharmacotherapy considers sex and naltrexone response-related genes.

In a new Yale study, researchers provided extensive data that gender differences in AUD and treatments may explain the lack of treatment response with naltrexone in some patients. For example, brain activity related to alcohol craving and future heavy drinking differs between the sexes, which could have implications for treatment. The brain circuits underlying alcohol craving and heavy drinking share some similarities between men and women, but there are also important differences, as the study reveals.

Previous research has shown individuals with AUD who experience strong alcohol cravings—the overpowering desire to consume alcohol—are more likely to relapse into heavy drinking. Researchers have also shown cravings can be triggered by stressful life events and alcohol-related cues, such as seeing other people drinking. What has been less clear is whether these patterns are the same in men and women. However, growing evidence indicates they might not be.

Says Sinha, “In the last two decades, there has been a very steep increase in binge drinking among women in the United States, much more so than in men. That has led to a lot more concern for comorbidities associated with alcohol use disorder, such as liver disease, cardiovascular issues, and cancer risk. So we set out to see if stress- and cue-related cravings differ in men and women.”

The May 2024 study utilizes fMRI scans to examine how men and women with AUD respond differently to stress and alcohol-related cues. The study found that while alcohol cues triggered stronger cravings in men, stress cues had a similar impact on women, suggesting the need for sex-specific treatment strategies.

When researchers looked at brain function while participants viewed images, they found that brain circuits—particularly those connected to emotion, reward, regulation of stress and emotion, and impulse control—responded differently in men and women. “We found women reported greater levels of stress after viewing stress cues than did men,” says Sinha. “Further, while alcohol cues led to stronger craving in men than the stress cues did, in women, stress and alcohol cues led to the same amount of craving in women. In women, those circuits were clearly blunted, but in men they were hyperactive.”

She added, “In women, disruptions in brain regions associated with anxiety were related to future heavy drinking.” These sex differences in craving and its underlying neural correlates suggest that men and women are different and require more targeted therapeutic approaches.

More Rapid Initiation of Treatment Is Best for Both Women and Men with OUD

Another new study on naltrexone used to treat opioid use disorder (OUD) found that patients on a rapid five-to-seven-day treatment were significantly more likely to receive a first injection of XR-naltrexone compared to those on the standard seven-to-15-day treatment procedure (62.7% vs. 35.8%). Withdrawal severity was generally low and comparable across the two groups. Starting people with OUD on extended-release, injectable naltrexone (XR-naltrexone) within five to seven days of seeking treatment is more effective than the standard treatment but requires closer medical supervision, according to results from an important recent JAMA study.

During this waiting period, patients are at high risk of returning to opioid use or overdosing or discontinuing treatment, a significant barrier to the implementation of long-acting naltrexone. This study makes it more likely long-acting opioid antagonists may be considered rather than opioid maintenance. The difference in waiting time may also make XR-naltrexone more viable than buprenorphine and methadone for some patients.

We have been treating AUD and patients with OUDs with the same treatment again and again, often blaming them for recidivism rather than providing a different treatment approach as we do in treatment-resistant depression. This mistake needs correcting.

As we move into the future, new treatments and learning more about genetic and gender-based responses to treatment for AUD, residential and outpatient treatment, and harm reduction, will become more effective. Dr. Rush talked about these in the eighteenth century, and they still exist today.


ReMaggioni E, et.al Brain volumes in alcohol use disorder: Do females and males differ? A whole-brain magnetic resonance imaging mega-analysis. Hum Brain Mapp. 2023 Sep;44(13):4652-4666. doi: 10.1002/hbm.26404. Epub 2023 Jul 12. PMID: 37436103; PMCID: PMC10400785.ferences

Sinha R. Alcohol’s Negative Emotional Side: The Role of Stress Neurobiology in Alcohol Use Disorder. Alcohol Res. 2022 Oct 27;42(1):12. doi: 10.35946/arcr.v42.1.12. PMID: 36338609; PMCID: PMC9621746.

Srivastava AB, Gold MS. Naltrexone: A History and Future Directions. Cerebrum. 2018 Sep 1;2018:cer-13-18. PMID: 30746025; PMCID: PMC6353110.

Ellison M, et. al. Reversal of Opioid-Induced Respiratory Depression in Healthy Volunteers: Comparison of Intranasal Nalmefene and Intranasal Naloxone. J Clin Pharmacol. 2024 Mar 4. doi: 10.1002/jcph.2421. Epub ahead of print. PMID: 38436495.