Ketamine’s potential to fight alcohol abuse has a major problem

For women, ketamine treatment might just replace one addiction with another.

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The drug ketamine is undergoing a major rebrand. Ketamine is famous for its power to give the user a distinctive “trance-like” experience, but the hallucinogenic is attracting attention for its potential to treat conditions like depression, post-traumatic stress disorder, and other psychological conditions..

Ketamine may have another — somewhat counterintuitive — benefit, too. In the future, the drug could help treat alcohol addiction. In fact, it could help keep alcoholism at bay for years, a new study in rats suggests. But there is a catch: The results might only apply to men.

The research, published in the journal eNeuro, shows that ketamine curbs the desire to drink alcohol in male rats and reduced their alcohol intake for three weeks after the treatment ended.

“Three weeks is a long time in a rat life,” Mohamed Kabbaj, a professor of neuroscience at Florida State University and an author on the study, says. “If similar things happen in humans, one could imagine that after a short treatment with ketamine, alcoholic patients will cease alcohol intake for a couple of years.”

Ketamine has potential as a long-lasting alcohol abuse treatment for men, but for women there are big unanswered questions. 

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Ketamine’s potential as a medication

Alcohol abuse disorder affected 14.1 million adults in 2017. Treatment options are limited to support groups like Alcoholics Anonymous, and three drugs approved for use in the United States. But there is no guarantee that any of these treatments will work for any one individual.

If this new work holds up, there’s potential that ketamine could become a fourth drug treatment for alcohol abuse.

Though this study was done in rats, there are clinical trials being done in humans, too. One 2018 phase II trial looked at how ketamine impacts alcohol use and depression — the researchers published a related paper earlier this year suggesting ketamine could help reduce the risk of addiction among people with depression who are at-risk of substance abuse. Other ongoing human trials are investigating whether ketamine could help prevent relapse in alcoholics who have given up drinking.

This research combined with the US Food and Drug Administration’s willingness to consider ketamine for depression signal that the agency is taking the drug seriously as a therapeutic treatment, Kabbaj adds. (Ketamine is a schedule 3 drug in the US, meaning it is considered to have some potential medical use.)

"Three weeks is a long time in a rat life"

“Ketamine was approved recently by FDA for treatment of depression and thus, if the ongoing clinical trials for the use of ketamine in the treatment of alcoholism are conclusive, ketamine could be an approved drug for alcoholism treatment,” he says.

But there’s a major catch. Ketamine may not work the same way for males and females. In fact, for females there’s evidence that using ketamine to treat alcohol abuse disorder could saddle people with a new addiction: a craving for ketamine instead.

The problem with ketamine for alcohol abuse disorder

In Kabbaj’s experiment, the scientists team divided the rats based on how much alcohol they drank at will, separating them into “high drinking” and “low drinking” groups. Then they tested how small doses of ketamine affected the rats’ behavior.

For the high-drinking male rats, ketamine reduced their drinking. Interestingly, the drive to drink remained blunted three weeks after treatment ended. But in the hard-drinking female rats there were no changes in drinking after they received ketamine. In the low-drinking female rats, alcohol use increased.

A ketamine-based drug is approved to treat depression, but for alcohol abuse it's differing effects on males and females is a sticking point.

All of the rats in this experiment showed an “incubation of ketamine craving,” suggesting that they did form some kind of attachment to it. But female rats showed a stronger preference for ketamine than the male rats, suggesting that they started to crave the drug more.

If ketamine is used at a “low dose and in limited fashion,” individuals shouldn’t develop a craving for it, Kabbaj says. But the evidence suggests more research needs to be done on how ketamine addiction may develop in women specifically.

“It could be simply differences in alcohol and ketamine metabolism, as those two drugs linger around longer in the brain of females compared to males — this is true in humans as well — or it could be that the ketamine dose we used was perfect for males but not females,” says Kabbaj.

“We need to use more doses of ketamine in females and see if there is an ideal dose in this sex.”

The researchers plan to delve deeper into the possible sex differences in reaction to ketamine. At least three ongoing trials investigating ketamine for alcohol abuse are open to women participants, which should help shed more light on the topic, too.

Ultimately, Kabbaj is hopeful that ketamine could treat alcohol abuse. It could be a long-lasting treatment that “will give hope to millions of alcoholics and their families that there is light at the end of the tunnel,” he says.

But for the women among those millions, there are still some big lingering questions that need answers.

Clinical and preclinical studies have shown that ketamine, an NMDA-receptor antagonist, has promising therapeutic value for the treatment of alcohol use disorder (AUD). However, maintenance of remission will ultimately require repeated infusions of ketamine which may lead to abuse potential and may hinder its therapeutic benefits. It is therefore crucial to assess the effects of repeated treatments with ketamine on alcohol intake. Accordingly, this study aimed to examine in both sexes how individual differences in alcohol intake alter ketamine self-administration and how ketamine self-administration will alter subsequent alcohol drinking behaviors. Male and female rats intermittently drank alcohol or water for 10-weeks and were divided into high- or low-alcohol intake groups prior to ketamine self-administration. Rats self- administered ketamine under fixed and progressive ratios schedules of reinforcement from weeks 4-7, and incubation of ketamine craving was examined from weeks 8-10. To investigate structural plasticity in a brain region involved in reward, nucleus accumbens (NAc) dendritic spine morphology was examined. Our results show that high-alcohol intake in male rats attenuated ketamine self-administration whereas in female rats, high-alcohol intake enhanced motivation to self-administer ketamine. Ketamine reduced alcohol intake in high-alcohol male rats but increased it in low-alcohol female rats. Incubation of ketamine craving developed in all groups except low-alcohol females. 3-weeks abstinence from ketamine was associated with increased mushroom spines in all groups except the high-alcohol male group. Overall, these data suggest that ketamine as a treatment for AUD may benefit male but not female subjects and warrants further investigation before use as a therapeutic agent.

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