“ADHD Could Mask Warning Signs of Alcohol Dependency, Rodent Study Suggests”

New research raises concerns about the co-use of prescription stimulants and alcohol in adolescents with ADHD. The study, published in the American Journal of Drug and Alcohol Abuse, found that adolescent rats exhibiting ADHD-like symptoms tend to be resistant to developing alcohol withdrawal symptoms, especially when alcohol is consumed alongside amphetamine. This resistance could obscure warning signs of alcohol dependency.

The study was driven by growing concerns over the non-medical use of amphetamine-based stimulants prescribed for ADHD, especially when these medications are mixed with alcohol. Adolescents and young adults are particularly vulnerable during this critical period of brain development, exhibiting higher tendencies toward binge drinking and misuse of stimulant medications. Research indicates that individuals who use stimulants without a prescription are more inclined to combine them with alcohol, leading to heavier drinking episodes and heightened risks of substance abuse.

Combining stimulants like amphetamines with alcohol is especially troubling because stimulants can counteract the sedative effects of alcohol. This interaction may result in increased alcohol consumption without individuals recognizing the potential harm. Given that individuals with ADHD are at an elevated risk for developing substance use disorders, including alcohol use disorder, the researchers sought to investigate whether the attenuation of alcohol withdrawal symptoms observed in general populations also occurs in an ADHD model.

"I have long been interested in the combined use of alcohol and other drugs, especially stimulants like caffeine and amphetamine. I am also interested in how the still-developing brain of adolescents responds to drugs. Over the last few decades, there have been increases, particularly among older adolescents, in the off-prescription (i.e., non-medical) use of amphetamine-based drugs that are commonly prescribed to individuals with a diagnosis of ADHD," said study author Dennis E. Rhoads, professor emeritus of biology at Monmouth University.

"Because people have admitted to combining these with consumption of alcoholic beverages, we modeled adolescent combined use of amphetamine and alcohol in rats and discovered that the co-administration of amphetamine decreased subsequent alcohol withdrawal symptoms. In humans, appearance of alcohol withdrawal symptoms can serve as a cue of a developing alcohol use disorder, and thus, these cues are altered if someone is regularly using a stimulant with alcohol. Given this discovery, we wondered how the ADHD-brain, for which amphetamine is therapeutic, would respond to the use of amphetamine and alcohol, alone and in combination."

To investigate this, the researchers used three strains of adolescent rats: Spontaneously Hypertensive Rats (SHR), Long-Evans (LE) rats, and Wistar Kyoto (WKY) rats. SHR rats are often used to model ADHD due to their overactivity, impulsiveness, and difficulty maintaining sustained attention, which are traits associated with ADHD. The WKY strain served as a genetic control for the SHR rats, while the LE strain was included to provide an additional comparison.

The researchers used liquid diets to administer ethanol (alcohol), amphetamine, or a combination of the two to the rats over a period of up to 26 days. The rats were divided into four groups: a control group with no added substances, an ethanol-only group, an amphetamine-only group, and a group consuming both ethanol and amphetamine.

At various intervals-after 5, 12, 19, and 26 days of diet consumption-the rats were observed for signs of alcohol withdrawal. These signs included reduced movement (hypoactivity) and anxiety-like behavior, which were assessed using special activity chambers that allowed the researchers to measure how much the rats moved and how they behaved in a light-dark environment, a common test for anxiety in animals. The severity of withdrawal was scored on a scale based on the presence of behaviors such as tremors, hyperactivity, and convulsions.

One finding was that the SHR rats (the model for ADHD) showed a remarkable resistance to developing the more severe alcohol withdrawal symptoms seen in the other two strains. While all three strains showed hypoactivity (reduced movement) during alcohol withdrawal, the SHR rats did not progress to more severe symptoms like convulsions or anxiety-like behavior. In contrast, the LE and WKY rats displayed these severe withdrawal symptoms.

The researchers "were surprised to find that these rats did not develop the common alcohol withdrawal symptoms," Rhoads told PsyPost. "The major discovery was the absence here of the expected alcohol withdrawal symptoms even after long periods of alcohol consumption."

Another important finding was that co-consumption of amphetamine with alcohol had different effects depending on the strain. For the LE and WKY rats, co-consumption of amphetamine significantly reduced the severity of alcohol withdrawal symptoms, including hypoactivity and anxiety-like behavior. However, for the SHR rats, amphetamine co-consumption did not appear to have any effect on withdrawal severity - it neither increased nor decreased the symptoms.

"People who are regularly using a stimulant with alcohol may show less of the alcohol withdrawal symptoms that would otherwise serve as a cue that they are developing an alcohol use disorder, i.e., a clear sign that they are drinking too much, too often. However, some individuals with a diagnosis of ADHD may naturally exhibit fewer alcohol withdrawal symptoms. Thus, this important symptom of an emerging alcohol use disorder may be missing."

But the study, like all research, includes some caveats. The study was conducted on rats, which, while useful models for understanding human behavior, are not perfect stand-ins for human experiences with alcohol and stimulants. "Adolescents of the Spontaneously Hypertensive Rat (SHR) show specific behaviors that led other investigators to develop them as a model for studying ADHD, or at least some sub-population of individuals with this diagnosis," Rhoads noted. "Our findings are based on comparing SHR to other strains of rats."

Further research in humans is necessary to determine whether people with ADHD, particularly those who regularly take amphetamine-based medications, might similarly experience a lack of warning signs for alcohol use disorder due to reduced withdrawal symptoms.

Looking ahead, Rhoads outlined two goals for this line of research: "One is to continue studying SHR to understand why they do not develop the alcohol withdrawal symptoms typically observed when rats are consuming alcohol. Is there something different about how their brain adapts (or does not adapt) to the presence of alcohol?"

"The second is to determine if there is translational value of this study for humans, particularly in the case of ADHD. Is there any evidence that alcohol withdrawal symptoms are sometimes attenuated in individuals with an ADHD diagnosis? There have been a number of studies of the co-occurrence of ADHD and alcohol use disorder, but more detail is needed about the specific symptoms of alcohol withdrawal."

The study, "Alcohol withdrawal and amphetamine co-use in an animal model for attention deficit hyperactivity disorder," was authored by Pooja M. Shah, Nicholas R. Pillarella, Marta Telatin, Natalie C. Negroni, Jessica N. Baals, Grace L. Haemmerle, Bruno T. Pillari, and Dennis E. Rhoads.

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