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The effects of ketamine differ depending on gender

Summary: The effects of ketamine on depression and pain, as well as its interaction with opioid pathways, differ significantly between the sexes. In a detailed study in rats, the team found that blocking opioid receptors reversed the impact of ketamine only in men, suggesting a complex interaction between ketamine, opioid systems and sex hormones.

This finding highlights the need to consider gender in ketamine treatment strategies and could explain previous inconsistencies in ketamine research. The results also suggest that testosterone may inhibit men’s ability to compensate for blocked opioid receptors, unlike women, who increase opioid receptor density in response.


  1. Blocking opioid receptors in the brain counteracts the effects of ketamine in male rats, but not in female rats, indicating sex-specific pathways.
  2. The study used functional ultrasound imaging to observe how naltrexone pretreatment differently affects ketamine-induced brain activity in male and female rats.
  3. Removal of testosterone in male rats eliminated the differential response to ketamine when opioid receptors were blocked, indicating a hormonal influence on the drug’s effects.

Source: Stanford

Ketamine, increasingly popular as a treatment for depression and pain, is often prescribed as an alternative to addictive opioids. But the data is mixed on whether ketamine’s effects rely on brain pathways similar to those of opioids.

New research from Stanford Medicine scientists suggests that the confusion may be linked to an overlooked factor: gender.

In a rat study, researchers found that blocking opioid receptors in the brain extinguished the effects of ketamine, but only in male rats. The female rats’ response to ketamine remained largely the same.

“The main thing we’re interested in is whether there is a functional interaction between ketamine and the opioid system,” said Raag Airan, MD, Ph.D., assistant professor of radiology, referring to receptors in the brain that bind to opioids. .

Airan is the lead author of a study published January 30 in Natural communications describing the results. The study confirms that ketamine and opioids share common brain pathways, at least in some circumstances.

It’s further evidence that “ketamine is a very strange drug,” Airan said, and that we need to be cautious about the enthusiasm around prescribing ketamine for a wide variety of conditions.

Ketamine is generally known as an NMDA receptor antagonist, meaning it blocks receptors for the neurotransmitter glutamate, although other NMDA receptor antagonists do not have the therapeutic effects of ketamine.

In 2018, a small clinical trial by Stanford Medicine researchers found that the antidepressant effects of ketamine could be removed by first giving patients naltrexone, a drug that blocks opioid receptors. The study sparked controversy in the field.

Airan, whose lab developed ways to precisely deliver ketamine into the brain, was inspired to replicate the clinical trial in rats, which would allow a closer look at what’s happening in the brain.

Results may vary

Initially, the Airan team wasn’t looking for gender differences. Tommaso De Ianni, Ph.D., a former postdoctoral fellow in Airan’s lab and lead author of the study, tested a group of rats and found that, indeed, naltrexone appeared to block the effects of ketamine on the areas brain disorders linked to depression and reward processing.

But to his dismay, when he repeated the experiment in a second group, the naltrexone was found to have no effect. Looking at the details of the experiments, De Ianni and Airan realized that there was only one difference: the first group consisted of only male rats and the second group consisted of only female rats.

“Honestly, it was a surprise,” Airan said. “We saw a very clear difference between the sexes. The change was quite marked among men, but not among women.

To study this unexpected difference, researchers designed a trial to compare male and female rats receiving three different drug combinations: naltrexone followed 10 minutes later by ketamine, saline (as placebo) followed by ketamine and naltrexone followed by saline.

This was a crossover trial, meaning each animal would receive the three combinations in random order, separated by a one-week waiting period.

Using functional ultrasound imaging, a relatively new technique that maps, in high resolution, brain activity in awake animals, the researchers found that in male rats, naltrexone blocked changes in neuronal activity induced by ketamine, including in brain areas involved in depression, such as the medial prefrontal cortex and reward processing, such as the nucleus accumbens and lateral habenula.

In female rats, naltrexone pretreatment caused no statistically significant changes in ketamine-induced brain activity.

The researchers also found that if they surgically removed the male rats’ testicles, thereby eliminating their source of testosterone, the naltrexone pretreatment lost its effect and the male rats reacted the same way as the female rats.

The team then compared the physiological changes in the brain. Ketamine is known to reverse the loss of synapses, or neuronal connections, often seen in depression and stress-related disorders, a phenomenon that researchers have confirmed in both male and female rats. However, when male rats were pretreated with naltrexone, ketamine lost its synapse-restoring powers. Again, female rats showed no significant changes.

The researchers also observed differences in behavior. Repeated consumption of ketamine typically causes increased physical activity in animals, known as locomotor sensitization. This behavior was also blocked in male rats treated with naltrexone before ketamine, but not in female rats.

All of these results indicate that ketamine depends, at least in part, on the opioid system, Airan said. “We believe there is now compelling imaging, physiological and behavioral data that supports that indeed ketamine and the opioid system interact, and that there is functional relevance.”

It would be important to take these interactions into account when treating patients. “What happens if someone has depression, but is also taking opioids for chronic back pain? » » asked Airan. “Would they respond differently to ketamine treatment for depression?

Women compensate

As for how female rats still experience the effects of ketamine with the opioid blocker, researchers believe their brains are able to compensate by simply developing more opioid receptors.

When they compared the brains of male and female rats repeatedly treated with naltrexone, they found that the females had increased opioid receptor density, bypassing the blockade. Perhaps in male rats, testosterone somehow limits their brains’ ability to develop more opioid receptors.

“It’s possible that testosterone blocks this compensatory response,” Airan said, “meaning that the male brain without testosterone would compensate, but with testosterone on board, that’s not the case.”

His team plans future studies to explore this question, among many others raised by the new study. What would happen if they gave estrogen to male rats, for example, or testosterone to female rats?

Not accounting for gender may have contributed to the inconsistent data on ketamine’s interaction with the opioid system, Airan said. Few other studies of ketamine have focused on gender as a variable. In preclinical experiments, although efforts are being made to include more female animals, male animals are still used more frequently. Most studies of ketamine in humans have too few participants to show a statistically significant difference between the sexes.

“In our clinical trial designs, we need to be able to take biological variables like sex into account, and we need to look at them,” Airan said. “We can’t just assume, ‘Oh, it’s probably good.'”

About this neuropsychopharmacology research news

Author: Nina Bai
Source: Stanford
Contact: Nina Bai–Stanford
Picture: Image is credited to Neuroscience News

Original research: Free access.
“Sex dependence of opioid-mediated responses to subanesthetic ketamine in rats” by Tommaso Di Ianni et al. Natural communications


Sex dependence of opioid-mediated responses to subanesthetic ketamine in rats

Subanesthetic ketamine is increasingly used for the treatment of various psychiatric conditions, both on-label and off-label. Although it is commonly classified as a NOT-methyl D-aspartate (NMDAR), our picture of the mechanistic underpinnings of ketamine is incomplete.

Recent clinical evidence has controversially indicated that a component of the effectiveness of subanesthetic ketamine may be opioid dependent. Using pharmacological functional ultrasound imaging in rats, we found that opioid receptor blockade suppressed neurophysiological changes evoked by ketamine, but not by a more selective NMDAR antagonist, in limbic regions implicated in the pathophysiology of depression and in the processing of rewards.

Importantly, this opioid-dependent response was highly sex-dependent, as it was not evident in female subjects and was fully reversed by surgical removal of male gonads. We observed similar sex-dependent effects of opioid blockade affecting ketamine-evoked postsynaptic density and behavioral sensitization, as well as opioid blockade-induced changes in opioid receptor density.

Together, these results highlight the potential of ketamine to induce its affective responses via opioid signaling and indicate that this opioid dependence may be strongly influenced by the sex of the subject. These factors should be assessed more directly in future clinical trials.

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