Acetaminophen, ADHD, and Autism

Several studies, over the last five years, have reported an association between a woman’s use of acetaminophen during pregnancy and the incidence of attention deficit hyperactivity disorder (ADHD) and related conditions in her offspring. Acetaminophen, aka paracetamol, is a commonly used pain reliever and fever reducer found in multiple over-the-counter products, most notably Tylenol. Rodent studies indicate that acetaminophen can affect neurodevelopment; the drug is toxic to cortical neurons and inhibits fetal testosterone production, “which would critically disrupt brain development,” according to Yuelong Ji et al. Still, regulatory agencies have largely ignored the studies, possibly because they have relied on women’s self-reports instead of using more objective, precise data. Two recent studies have attempted to provide more concrete data.

A 2020 study, led by Brennan H. Baker, followed 345 children whose mothers were enrolled during the first prenatal visit or at delivery, between September 25, 2007, to September 10, 2009, at the Centre Hospitalier Université de Sherbrooke in Sherbrooke, Québec, Canada. Acetaminophen content in meconium samples, collected during delivery, was used to assess prenatal exposure. The presence of ADHD issues was determined around age six-and-a-half, using physician diagnosis/medical records and the Behavioral Assessment System for Children Parent Report Scale. Between ages nine to 11, the children underwent magnetic resonance imaging to assess resting-state brain connectivity.

The Canadian researchers found acetaminophen in 199 meconium samples (57.7%) and an ADHD diagnosis in 33 of the 345 children (9.5%): “Compared with no acetaminophen, detection of acetaminophen in meconium was associated with increased odds of ADHD (odds ratio [OR], 2.43; 95% CI, 1.41-4.21).” MRIs from children whose meconium contained acetaminophen showed less connectivity between frontoparietal and default mode network nodes and sensorimotor cortices, “which mediated an indirect effect on increased child hyperactivity (14%; 95% CI, 1%-26%).”

In the second study, researchers measured acetaminophen and two of its metabolites (acetaminophen glucuronide and 3[N-acetyl-L-cystein-S-yl]-acetaminophen) in cord plasma to assess exposure. The 996 mother-infant pairs in this prospective study gave birth at Boston Medical Center and were part of the Boston Birth Cohort. In addition to multiple clinical and demographic variables, the researchers compared metabolite levels to physician diagnoses in electronic medical records for ADHD only (n=257; 25.8%), autism syndrome disorder (ASD) only (n=66; 6.6%), both ADHD and ASD (n=42; 4.2%), other mental, behavioral, and developmental disorders (n=304; 30.5%), and children without any of these diagnoses (n=327; 32.8%) in their records.

All of the cord samples in this study had detectable acetaminophen. So they did not have an unexposed group to act as a control. The researchers found a direct association between acetaminophen/metabolite levels and ADHD and ASD—but not other developmental orders. When comparing cord acetaminophen levels in the second and third tertiles to the first tertile, the odds ratio (OR) of having an ADHD diagnosis was 2.26; 95% CI, 1.40-3.69 (second tertile) and 2.86; 95% CI 1.77-4.67 (third tertile). Compared to the first tertile, the odds ratio of an ASD diagnosis was 2.14; 95% CI, 0.93-5.13 (second tertile) and 3.62; 95% CI, 1.63-8.60 (third tertile).

The authors list several limitations of their study, including the one-time cord plasma measurement that cannot reflect acetaminophen exposure at various times during the pregnancy: “Whether there is a specific time window when the developing brain is most sensitive to acetaminophen exposure remains unclear.” Also, the study design did not include possible confounders stemming from genetic or environmental factors.

The authors of the Boston study say their findings “warrant addition investigations.” Baker and his Canadian colleagues are more precautionary; they say, “…this work suggests caution should be used in administering acetaminophen during pregnancy. Research into alternative pain management strategies for pregnant women could be beneficial.”

Baker BH, et al. Association of Prenatal Acetaminophen Exposure Measured in Meconium with Risk of Attention-Deficit/Hyperactivity Disorder Mediated by Frontoparietal Network Brain Connectivity. JAMA Pediatr. September 28, 2020.

Ji Y, et al. Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure with Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood. JAMA Psychiatry. 2020;77(2): 180-189.

Cannabis Use and Risks to Youth

As cannabis for medical and recreational use has become legal in more states, the perception that it is harmful has decreased. Recent studies, however, are showing that easy access to cannabis, specifically recreational cannabis with high THC levels, is dangerous—especially for young people.

On April 28, 2021, The Denver Post reported about the increase in psychotic symptoms among teens and young adults who are consuming too much high-potency cannabis. Colorado, along with Washington state, legalized recreational cannabis in 2012. Since that time, cannabis use has evolved from smoking and ingesting the botanical (e.g. in brownies) to “dabbing” oils and vapors that have high concentrations of the psychoactive component THC (tetrahydrocannabinol).

A 2020 review, led by Shweta J. Patel, looked at the relationship between cannabis use and schizophrenia, a condition with psychotic symptoms that include delusions and hallucinations. They searched for human studies published in peer-reviewed journals between 2015 and March 2020, assessed their quality, and ended up with 12 articles: five traditional reviews, two systematic reviews, two meta-analyses, and three observational studies. Ten of the 12 concluded that cannabis use, primarily due to THC content, may be a causative factor for schizophrenia—particularly “in genetically predisposed or at-risk populations.” In people with schizophrenia, THC exacerbates symptoms. In addition to psychosis-like symptoms, THC impairs memory and the ability to concentrate. Adolescents with their still-developing brains are at greater risk: “Younger and more frequent users are at higher risk of developing cognitive decline. Adolescent cannabis use impacts cognition in the future.” Unfortunately, cannabis use is increasing most quickly among high school students.

It is inaccurate, however, to say that the relationship between cannabis and schizophrenia is all bad. Patel et al report that the cannabis-derivative cannabidiol (CBD) has lessened psychotic symptoms in some people with schizophrenia. CBD reduces THC’s effects. As they point out, “Cannabis has many strains with different ratios of components. The ratio of THC and CBD is the most important psychotomimetic [producing psychotic-like symptoms] property of any cannabis strain”—which leads back to the problems in Colorado.

“’Use and misuse has not only become increased at an alarming rate—we’re seeing it in younger and younger populations,’” the legislative co-chair for the Colorado Association of School Nurses told journalist Alex Burness. And this is not about smoking a joint or consuming brownies. The use of vaporized high-THC concentrate—as high as 90%–has increased. Four years ago, 20% of young cannabis users reported “dabbing.” In the most recent Colorado survey, 52% of users reported dabbing in the previous 30 days. Parents in the article report psychotic behavior in their children.

The economic windfall from cannabis sales and the emphasis on cannabis’ medicinal properties are making it difficult to address the issue of overuse by the young. Colorado state representative Yadira Caraveo, a pediatrician, unsuccessfully proposed legislation to limit THC content to 15%. Much of the cannabis sold in the state has THC content above 15%, and legislators are unwilling to curtail the state’s cannabis industry. Marijuana legalization is clearly a two-edged sword; and the THC-CBD ratio lies at the heart of it.

Burness A. Colorado reckons with high-potency marijuana and its impact on children. The Denver Post. April 28, 2021.

Patel SJ, et al. The Association Between Cannabis Use and Schizophrenia: Causative or Curative? A Systematic Review. Cureus. July 21, 2020.

Gamma Sensory Flicker and Alzheimer’s

Researchers at Georgia Institute of Technology and Emory University conducted a small feasibility study to test the safety and effect of a gamma flicker device on ten people with mild cognitive impairment due to Alzheimer’s disease (AD). Exposure to flickering light and sound at gamma frequency (40 Hz) stimulates neural activity in the brain and reduces amyloid pathology, according to experiments with mouse models of Alzheimer’s disease. Gamma flicker also affect microglia, the brain’s primary immune cells.

In this randomized study, the participants used the flicker device, one hour a day at home, for either eight weeks or four weeks (delayed start protocol). The device consisted of light-emitting goggles and sound-emitting headphones, flickering at a repetition rate of 40 Hz. Participants were contacted each week by phone. Adherence to the protocol averaged above 88% over the eight weeks. EEG activity, measured before and after four weeks of no flicker, four weeks of device use, and eight weeks of device use, showed 40 Hz entrainment.

Participants also underwent fMRI to assess connectivity between areas of the brain, affected in Alzheimer’s. After eight weeks of daily flicker, the functional connectivity between the posterior cingulate cortex (PCC) and precuneus (PCu), which is weakened in AD, was stronger (p=0.016). The authors say that “…a prior small study showed PCC-PCu functional connection strength was positively correlated with cognitive function.” The researchers also assessed immune data from participants cerebrospinal fluid and found a downward trend in several cytokines and immune factors, including the cytokine TWEAK (tumor necrosis factor-related weak inducer of apoptosis; p=0.04) after eight weeks of treatment.

Adverse events were dizziness (n=3), tinnitus (n=1), and headache (n=1). The authors excluded people with a history of migraines, tinnitus, or seizures from the study because sensory stimuli could incite or worsen these conditions.

For more information about the light’s therapeutic effects on the brain, take a look at Dr. Peter Newsom’s article “Photobiomodulation as a Treatment Modality for COVID-19 Sequelae” in this issue (page ?).

He Q, et al. A feasibility trial of gamma sensory flicer for patients with prodromal Alzheimer’s disease. Alzheimer’s Dement. May 13, 2021.

Low Intensity Pulsed Ultrasound and Brain Injury

Researchers in China, Taiwan, and Japan have published several animal studies on the use of low-intensity pulsed ultrasound (LIPUS) to heal various types of brain injury. LIPUS reportedly increases the production of brain-derived neurotrophic factor (BDNF) in astrocytes and promotes nerve regeneration. It has also increased neurotrophins and vascular endothelial growth factor, lessening dementia in mouse models.

The use of LIPUS to address brain injuries and dementia is being investigated by a “leader in cardiovascular science,” Hiroaki Shimokawa, MD, PhD. Dr. Shimokawa developed the first animal model of coronary artery spasm and researched endothelium-derived relaxing factors for over four decades. He developed a LIPUS machine, with the help of a Japanese-US company, that stimulated NO release from endothelial cells and promoted angiogenesis as a treatment for myocardial infarction and heart failure. Given that impaired vascular endothelial function is a risk factor for dementia and that LIPUS has shown benefits on the brain in other studies, Dr. Shimokawa and his team conducted a 2018 study that showed whole-brain LIPUS therapy (1.875 MHz, 6.0 kHz, 32 cycles) “markedly improves cognitive dysfunctions without serious side effects in the two major mouse models of dementia (vascular dementia from carotid artery stenosis and an Alzheimer’s model].” Lipus improved cerebral blood flow, increased neurotrophins, and “significantly upregulated endothelium-related genes in RNA-sequencing and expression of endothelial nitric oxide synthase.” In the vascular dementia mice, LIPUS “significantly increased CD31-positive endothelial cells and Olig2-positive oligodendrocyte precursor cells.” In the Alzheimer’s model, LIPUS reduced amyloid-β plaque and Iba-1-positive microglias that are signs of the illness.

A second study using mice investigated the use of LIPUS to improve neurological recover from ischemic stroke. The researchers “applied LIPUS to the whole brain three times in the first week (days 1, 3, and 5) after middle cerebral artery occlusion””the LIPUS therapy significantly reduced the infarct size at day 28 compared with the Non-Lipus group (p=0.045). “the therapy also “markedly improved neurological functions compared with the Non-LIPUS group in the rotarod and tightrope tests.” LIPUS therapy that started 28 days after the “stroke” did not improve functional recover.

At this point, the use of low-intensity pulsed ultrasound therapy is still being investigated in the laboratory; I am not aware of any human clinical trials. Dr. Shimokawa’s team believe that LIPUS could be an effective, non-invasive therapy for stroke, dementia, as well as neurodegenerative diseases. May it be so.

Eguchi K, et al. Whole-brain low-intensity pulsed ultrasound therapy markedly improves cognitive dysfunctions in mouse models of dementia – Crucial roles of endothelial nitric oxide synthase. Brain Stimulation. 2018;11:959-973.

Ichijo S, et al. Low-intensity pulsed ultrasound therapy promotes recovery from stroke by enhancing angio-neurogenesis in mice in vivo. Scientific Reports. 2021;11:4958.