August 22, 2024

U.S. Population Study Finds Link Between Stimulant Medications and Male Hypogonadism, But Condition is Uncommon

The first-line treatment for ADHD in both adults and children is stimulant medication such as methylphenidate or amphetamines. These medications function by increasing bioavailability of the neurotransmitters dopamine and norepinephrine within the brain. Some animal studies have suggested these medications could impact gonadal function, and more specifically testosterone production. 

A U.S. study team accessed electronic medical records (diagnoses, procedures, medications, and laboratory values), as well as insurance claims for about 108 million patients from 76 healthcare organizations. They used these to assess the risk of long-term ADHD stimulant medication on developing a diagnosis of testosterone deficiency in males above the age of puberty. 

They compared 20-40-year-old men with a clinical diagnosis of ADHD and long-term exposure to ADHD stimulant medications – including methylphenidate, dextroamphetamine, lisdexamphetamine, amphetamine, and dexmethylphenidate – with ADHD patients who did not receive any medication. 

After adjusting for confounding factors, they compared 17,224 men with a diagnosis of ADHD who had received at least 36 prescriptions of ADHD stimulant medications with an equal number with a diagnosis of ADHD who never received any ADHD medications. 

ADHD patients on long-term stimulant medication had a roughly 1.75 times higher rate of subsequently being diagnosed with low testosterone levels within five years than unmedicated ADHD patients. 

The team also compared 17,217 men with a diagnosis of ADHD who had received at least 36 prescriptions of ADHD stimulant medications with an equal number of men without a diagnosis of ADHD.  

Again, patients on long-term stimulant medication had a 75% higher rate of subsequently being diagnosed with low testosterone levels within five years than matched individuals without an ADHD diagnosis. 

The team concluded, “Long-term ADHD stimulant medication use in men was found to be associated with a significant increase in relative risk for a subsequent testicular hypofunction diagnosis. This difference was found when compared to both those with ADHD not using pharmaceutical therapy and those without ADHD. These results indicate that impaired gonadal function is a potential side effect of stimulant medications.” 

Like other observational studies, this work provides an important signal that must be replicated and validated with other methods, especially those that rule out other sources of confounding not measured in this study.  Moreover, diagnoses of testosterone hypofunction in this study were relatively rare to begin with. The measured 0.5% increase in testicular hypofunction diagnosis for those on long-term stimulant medication versus those not on stimulant medication would only affect roughly one in two hundred of those on stimulant medication. This small increase in risk must be weighed against the well-documented benefits of these medications. 

Garett P. Ostdiek-Wille, Kyle C. Bavitz, Taylor P. Kohn, and Christopher M. Deibert, “Attention-deficit hyperactivity disorder medication use is associated with testosterone hypofunction–results from a national claims database analysis,” IJIR: Your Sexual Medicine Journal (2024), 36:403–407, https://doi.org/10.1038/s41443-023-00805-2

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Population Study: Stimulants Shown to Reduce Hospitalization and Suicidality

Swedish Population Study Suggests Stimulants Reduce Hospitalization and Suicidality, Have No Significant Effect on Work Disability

A meta-analysis of short-term, placebo-controlled, randomized clinical trials (Cortese et al. 2018), looking at both efficacy and safety, supported prescribing stimulants – methylphenidate use in children and adolescents and amphetamine use in adults – as first-choice medications. 

However, these were short-term studies, and they focused on relieving ADHD symptoms. What about longer-term outcomes, especially looking more broadly at functional impairment and overall quality of life? 

Sweden has a single-payer health insurance system that encompasses virtually every resident and is linked to national registers that enable researchers to conduct nationwide population studies. 

A joint Finnish-Swedish research team used Sweden’s registers to study outcomes for all individuals of working age, 16 to 65 years old, living in Sweden who had received a diagnosis of ADHD from 2006 through 2021. The resulting study cohort encompassed 221,714 persons with ADHD. 

The team adjusted for the following confounding variables: Genetics, baseline severity of symptoms, baseline comorbidities, temporal order of treatments (which medication was used as first, second, third, and so forth, including also nonuse of ADHD medications), time since cohort entry, and time-varying use of psychotropic drugs, including antidepressants, anxiolytics, hypnotics, mood stabilizers (carbamazepine, valproic acid, and lamotrigine), lithium, antipsychotics, and drugs for addictive disorders. 

With these adjustments, they discovered that amphetamine treatment was associated with a roughly 25% reduction in psychiatric hospitalization relative to unmedicated ADHD. Lisdexamphetamine was associated with a roughly 20% reduction, dexamphetamine with a 12% reduction, and methylphenidate with a 7% reduction. All four medications are stimulants

None of the non-stimulant medications – atomoxetine, guanfacine, clonidine – had any significant effect on psychiatric hospitalization. Nor did modafinil a drug that is not FDA approved for ADHD but is sometimes used when other drugs fail. 

Amphetamine was also associated with the greatest reduction in suicide attempts or deaths, with a roughly 40% decline relative to unmedicated ADHD. Dexamphetamine was associated with a roughly 30% decline and lisdexamphetamine with a roughly 25% decline. The stimulant methylphenidate was only associated with an 8% reduction, and modafinil had no significant effect. 

Surprisingly, non-stimulant medications were associated with significant increases in suicide attempts or deaths: 20% for atomoxetine, 65% for guanfacine, and almost double for clonidine

Amphetamine and lisdexamphetamine also reduced the risk of nonpsychiatric hospitalization by more than a third compared to unmedicated ADHD. Dexamphetamine was associated with a risk reduction of more than 25%, methylphenidate with 20% lesser risk.  

The non-stimulant atomoxetine was associated with a roughly 15% reduction in risk of nonpsychiatric hospitalization. But neither guanfacine nor clonidine had any significant effect. 

Turning to work disability, atomoxetine was the only ADHD medication associated with a reduction – a roughly 10% improvement. All other medications had no significant effect

The team concluded, “In this cohort study of adolescents and adults with ADHD, the use of medications for ADHD, especially lisdexamphetamine and other stimulants, was associated with decreased risk of psychiatric hospitalizations, suicidal behavior, and nonpsychiatric hospitalizations during periods when they were used compared with periods when ADHD medication was not used. Non-stimulant atomoxetine use was associated with decreased risk of work disability.” 

September 13, 2024

Meta-analysis: Efficacy of Antioxidant Therapy for ADHD

Network Meta-analysis Finds No Significant Evidence for Efficacy of Antioxidant Therapy for Treating ADHD

Noting that “Oxidative stress disrupts the structure and function of neurons in the prefrontal lobe of the brain,” and “Structural and functional impairments in the prefrontal cortex have been shown to be highly correlated with behavioral and emotional problems of ADHD,” a Chinese team at Dalian University set out to systematically evaluate the safety and efficacy of antioxidant therapy in children and adolescents with ADHD. 

The team’s systematic search of the peer-reviewed medical literature identified a total of 48 randomized controlled trials (RCTs) or prospective studies involving 12 antioxidant agents (resveratrol, pycnogenol, omega-3, omega-6, quercetin, phosphatidylserine, almond, vitamin D, zinc, folic acid, ginkgo biloba, Acetyl-L-carnitine) that met criteria for inclusion: 

  • Ages 18 or younger. 
  • Clinical diagnoses of ADHD. 
  • Minimum treatment duration of two weeks. 
  • Experimental group received antioxidant treatment. 
  • Control group received either a placebo, the stimulant medication methylphenidate, or a different antioxidant or combination of antioxidants. 

Treatment efficacy was measured through ADHD symptom scores using Conners’ parent rating scale (CPRS), Conners’ teacher rating scale (CTRS), ADHD rating scale-parent (ADHD RS-Parent), and ADHD rating scale-teacher (ADHD RS-Teacher), as well as secondary outcome indicators such as the Clinical Global Impressions scale (CGI) and Continuous Performance Test (CPT), relative to controls. 

None of the antioxidant therapies were significantly better than placebo.

One limitation is that no effort was made to assess publication bias. 

These results indicate that antioxidants should not be used for treating ADHD.

September 12, 2024

No Association Found Between Acetominophen Use During Pregnancy, Subsequent ADHD

Swedish Nationwide Population Study Finds No Association Between Acetaminophen Use During Pregnancy and Offspring ADHD

A 2021 consensus statement by an international group of scientists and clinicians (Bauer et al.) recommended that pregnant individuals “forego [acetaminophen] unless its use is medically indicated,” due to the potential risk of developmental disorders such as autism and attention-deficit/hyperactivity disorder (ADHD). 

A mostly Swedish research team, collaborating with a U.S. researcher, nevertheless noted that previous studies have been limited by: 

  • Confounding by indication, because acetaminophen is taken for infection, fever, and pain (including pain from autoimmune disease), which are themselves risk factors for neurodevelopmental disorders such as ADHD. 
  • Confounding by parental health and genetics, because neurodevelopmental disorders are highly heritable. 
  • Small sample sizes. 

Sweden has a single-payer health insurance system that includes virtually its entire population, and national registers that enable tracking the health history of mothers and their children, including their children’s siblings. 

The team used the Swedish registers to identify the roughly two-and-a-half million children born in Sweden from mid-1995 through 2019. They were also able to identify all siblings to be able to control for otherwise unmeasured familial and genetic confounding. 

Almost 186,000 of these children were exposed to acetaminophen during pregnancy.  

After adjusting for available known confounders, including (but not limited to) child sex and birthdate, mother’s age and medical history, use of any other painkillers, use of any psychoactive medications, country of birth, residential region, smoking status, highest household education, and disposable income, children exposed to acetaminophen during pregnancy were 7% more likely to be diagnosed with ADHD subsequently than those who were not exposed. 

However, roughly the same results were found for other painkillers, including aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and antimigraine medication.   High doses of acetaminophen did not produce any stronger association with subsequent ADHD than low dosage. 

Moreover, when confining results to siblings – 8,526 children who were exposed versus 87,679 who were unexposed – the association between acetaminophen use during pregnancy and subsequent offspring ADHD vanished altogether (and, again, at every dose level). The associations similarly vanished with every other painkiller medication.  

The Swedish team concluded, “Acetaminophen use during pregnancy was not associated with children’s risk of autism, ADHD, or intellectual disability in sibling control analyses. This suggests that associations observed in models without sibling control may have been attributable to confounding.” 

September 5, 2024