Women's Brains Hit Hardest by Long-term Stimulant Abuse

Liam Davenport

July 14, 2015

Long-term abuse of stimulant drugs is associated with significantly different effects on gray matter volumes (GMVs) in men and women and are correlated with behavioral differences, new research shows.

The study, which included men and women who had been abstinent from stimulants for longer than a year, indicated that women previously dependent on the drugs, including cocaine and amphetamine, had significant GMV reductions compared with control persons across numerous brain regions.

"Vast neuroanatomic changes observed in abstinent patients with stimulant dependence were present in women but not in men."

"In particular, structures involved in reward, learning, executive control, and affective processing pathways were affected: the insula, orbitofrontal cortex, anterior cingulate cortex, medial frontal gyrus, and nucleus accumbens," the investigators write.

"These changes correlated with drug use and behavioral measures and may help to explain differences in the clinical course of stimulant dependence in women compared with that in men," they add.

The study was published online July 14 in Radiology.

Chicken-or-the-Egg Question

"We've been studying substance dependence and brain changes for a long time, and we were interested in sex differences, as it's an area that hasn't been very well studied," study coauthor Jody Tanabe, MD, professor of radiology at the University of Colorado School of Medicine, Anschutz Medical Campus, told Medscape Medical News.

"There's been a lot on the fact that there are known developmental differences, and there are known differences between men and women in brain morphology, but there really had not been very many studies looking at how that might be modified by drugs," she added.

For the study, the researchers performed T1-weighted spoiled gradient-echo inversion recovery MRI scanning of the brains of 59 people (28 women and 31 men) who were previously dependent on cocaine, amphetamines, and/or methamphetamine for an average of 15.7 years and had been abstinent for an average of 13.5 months.

The team also examined 68 age- and sex-matched individuals (28 women and 40 men) who were not previously dependent on the drugs. The images were analyzed using voxel-based morphometric software, and the potential confounders age, education, and head size were taken into account.

Overall, women had a significantly greater mean GMV across the cerebral cortex, thalamus, and basal ganglia (P < .001) than men, with anatomically similar differences between male and female control persons.

Although there were no significant differences in GMV between male control persons and men with stimulant dependence (P = .625), women with stimulant dependence had a significantly lower GMV in a number of regions across the brain (P < .001).

Specifically, women with stimulant dependence had a significantly lower GMV in the frontal lobe (orbitofrontal cortex, medial frontal gyrus, superior frontal gyrus), limbic regions (insula, amygdala, cingulate gyrus), temporal lobe (temporal pole, uncus, parahippocampal gyrus, hippocampus, occipitotemporal gyri, superior temporal gyrus, middle temporal gyrus), and inferior parietal lobule.

Interestingly, the researchers found that there was a negative correlation between severity of drug use and GMV in the nucleus accumbens in women (P = .047 for the right nucleus accumbens, and P = .031 for the left nucleus accumbens), which was not seen in men (P = .737 and P = .349, respectively).

There were also negative correlations between frontal and temporal changes in GMV in women with stimulant dependence and behavioral approach on the Behavioral Activation System scale (P = .002), as well as impulsivity (P = .013) on the Barratt Impulsiveness Scale.

Dr Tanabe said the question of what underlies the connection between brain changes and behavioral differences is a "chicken-and-egg question, and unfortunately, our study can't answer the chicken or the egg."

"What we can say is that it suggests that there is some connection between what we can measure objectively and behavior."

"I think the other thing that could be at play here is that there's been evidence that women seek help at a different stage from men, and maybe they are more severe by the time they seek help."

"So there could be a bias in terms of when women enter into these treatment programs, as perhaps women tend to be much worse off when they enter drug treatment programs," she added.

One factor that could potentially explain the findings is hormonal differences between men and women.

"There is pretty good evidence that, at least in animal studies, the estrogen cycle affects animal sensitivity to reward," said Dr Tanabe. "The estradiol-to-progesterone ratio is thought to be very important, and work has shown that, for example, if you take smoking, it's harder for women to quit smoking during certain stages of the menstrual cycle, and that appears to be linked to how sensitive one is to reward or negative affect."

What is clear is that further research is needed. "I think one of the most interesting questions is the chicken–egg question," Dr Tanabe said.

"Girls' brains are different from boys', and we know they behave differently ― anyone who has kids knows that ― and there is a growing cadre of researchers who are focusing on the adolescence and the kids."

"I think what we need to do ― and in fact the NIH [National Institutes of Health] is embarking on these kinds of studies ― are studies to look at the entire trajectory. These are very complicated and expensive types of longitudinal studies, but I think that's really what we need to go forward to determine how much of this is preexisting, how much of it is just being born with an XY chromosome. We just don't know," she added.

Need for More Research in Women

Commenting on the findings for Medscape Medical News, Jodi Gilman, PhD, from the Department of Psychiatry, Massachusetts General Hospital, Boston, said she thought the study was a "very well-done study, [and] they are looking at a really important issue."

"Gender differences are critical in any kind of morphometric studies of brain volume because we know that men's brains and women's brains are not the same," she said.

"We've known this for a really long time, and researchers are just beginning to really appreciate how these differences might contribute to different trajectories," said Dr Gilman.

"Something else that's of critical importance to look at is not only structure but also how structure relates to function, because that's what people ultimately care about. They care about what they can do and what they can't do and how stimulant use changes behavior," she added.

A related question is how quickly brain function recovers compared with brain structural changes following cessation of substance use. Dr Gilman said: "Function drives structure and structure drives function, and so it's really hard to know what has to happen first."

"But I would imagine that there are a lot of acute effects when somebody stops using a drug ― on mood and anxiety and on something like impulsivity ― that might show a shorter recovery time than structural recovery."

Dr Gilman believes that to elucidate further regarding these changes and how they differ between men and women, it is crucial that both sexes be included in studies of the impact of substance use.

"Believe it or not, this is a new thing," she said. "A lot of clinical trials used to only include men, and...I think this study really illustrates that women's brains might be different."

Noting the parallels with the differential impact of alcohol use between men and women, Dr Gilman concluded: "We really need to increase our study of women's brains, as well as cardiac issues and other issues that may be affected by drug use in both sexes, as you might get different results."

This study was supported by grants from the National Institute on Drug Abuse. The authors and Dr Gilman report no relevant financial relationships.

Radiology. Published online July 14, 2015. Full text

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