All you need for ADHD -- is a cuppa Joe?

Exploring the past, present, and future of Attention Deficit Hyperactivity drugs.

Preamble: my past personal saga with ADHD drug regulation and development

Ciba-Geigy (merged with Novartis 1996) is the manufacturer of Ritalin. A daily medication, taken chronically and indefinately, into adulthood. It was their golden goose, laying many golden eggs, and projected to do so exponentially into the future, as more kids got diagnosed by school nurses. And FDA ODE Director Bob Temple was their in-house guard dog. No way would he ever let anything risk that drug franchise.

In 1995, as a medical officer in Cardio-Renal Division, I was tasked to evaluate the Medwatch adverse drug reports and annual reports for the approved NDA, clonidine. I was surprised to see sudden deaths occurring in children who were given the drug to offset the insomnia of Ritalin. Apparently, psychiatrists at Harvard decided to push whopping doses of clonidine, for this off-label indication. The NDA sponsor sent an official request to FDA that their label include a warning against this use; they did not want the bad press nor liability. I interrogated the MedWatch database, finding even more sudden deaths, compiled my findings, and dutifully filed them officially with the NDA documents.

Concurrently, NPR reported on these deaths in children. Bob Temple became aware of the ‘bad publicity’ and went on the warpath. He immediately blocked med officer access to the database. Then he marched over to me and ‘asked’ me to leave. I instead moved over to Anesthesia, Critical Care, Drugs of Abuse Division. But my days at the agency were limited. Within a year, I took a Chief Medical Officer job at a local startup, Pharmavene.

As for Bob Temple, he was hauled in front of Senator Chuck Grassley’s committee and challenged to explain why he refused to inform the public of the dangers. Somehow ... Grassley had gotten all the data, and knew where to find it filed. Bob promptly added the warning to the clonidine label, though Ritalin’s remained untouched.

[That was my first federal whistleblower event.]

My past actions impacted the path of my career. At Pharmavene, after getting the Carbatrol NDA approved and then sold to Athena Neurosciences, the company was taken over by Shire Pharmaceuticals. Soon after, they bought Richwood Pharmaceuticals and their product Adderall, intending to make the extended release formulation at Pharmavene.

My FDA history was deemed detrimental to their future plans. I was ousted with a meager severance package. However, I used it to launch my own consulting firm, BioMedWorks, in late 1997.

Present Prevalence

ADHD is the most common psychiatric disorder diagnosed in children. A 2020 national survey found that 9.3% (5.6 million) of children in the United States, have the diagnosis. Methylphenidate and mixed amphetamine salts, are the most commonly prescribed drugs for the indication.

The most prevalent side effects are sleep problems and decreased appetite. A recent study showed children and young people taking methylphenidate for ADHD were around 2.6 times more likely to have sleep problems and 15 times more likely to have a decreased appetite than those not taking the drug. Headache and abdominal pain are common. Not surprisingly, height and weight means are reduced as well.

A case-control study from this current year found that long-term exposure to ADHD medications was associated with an increased risk of cardiovascular diseases, especially hypertension and arterial disease.

Children taking these psychostimulant drugs for attention deficit hyperactivity disorder (ADHD) who experience a common childhood fracture, take longer to heal than children who don't take these drugs. The longer they took the drug, the lower their bone density [up to as much as 52% less] compared to controls. This, too, is consistent with their lower body mass. And preclinical work found that bone strength and density were weakened in rats administered these drugs.

Future Use ?

Researchers are searching for better alternatives for attention disorders. One well studied compound is caffeine. A recent report summarized a meta analysis of all preclinical studies, with encouraging conclusions. Could this be the solution we need?

Abstract: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity. ADHD impairments arise from irregularities primarily in dopamine (DA) and norepinephrine (NE) circuits within the prefrontal cortex. Due to ADHD medication’s controversial side effects and high rates of diagnosis, alternative /complementary pharmacological therapeutic approaches for ADHD are needed. Although the number of publications that study the potential effects of caffeine consumption on ADHD treatment have been accumulating over the last years, and caffeine has recently been used in ADHD research in the context of animal models, an updated evidence-based systematic review on the effects of caffeine on ADHD-like symptoms in animal studies is lacking. To provide insight and value at the preclinical level, a systematic review based on PRISMA guidelines was performed for all publications available up to 1 September 2021. Caffeine treatment increases attention and improves learning, memory, and olfactory discrimination without altering blood pressure and body weight. These results are supported at the neuronal/molecular level. - JC Vázquez et al.

In the meantime, the field is examining other neurotransmitter systems: GABA and acetylcholine. This combination of neurotransmitters regulates attention span. The opposing actions of the neurotransmitters (acetylcholine and GABA) on neurons in the claustrum enable brain signals to be encoded efficiently, allowing the brain to pay attention and ignore noise.

The cholinergic system of the basal forebrain plays an integral part in behaviors ranging from attention to learning, partly by altering the impact of noise in neural populations. The circuit computations underlying cholinergic actions are confounded by recent findings that forebrain cholinergic neurons corelease both acetylcholine (ACh) and GABA. We have identified that corelease of ACh and GABA by cholinergic inputs to the claustrum, a structure implicated in the control of attention, has opposing effects on the electrical activity of claustrum neurons that project to cortical vs. subcortical targets. These actions differentially alter neuronal gain and dynamic range in the two types of neurons. In model networks, the differential effects of ACh and GABA toggle network efficiency and the impact of noise on population dynamics between two different projection subcircuits. Such cholinergic switching between subcircuits provides a potential logic for neurotransmitter corelease in implementing behaviorally relevant computations. - A Nair, et al.

I will continue to pay attention, seeking out better ways for our woes.

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REFERENCES

JAMES M. SWANSON, DAVID FLOCKHART, DAN UDREA, DENNIS CANTWELL, DANIEL CONNOR, LILLIE WILLIAMS. Clonidine in the Treatment of ADHD: Questions about Safety and Efficacy. Journal of Child and Adolescent Psychopharmacology.Jan 1995.301-304. https://doi.org/10.1089/cap.1995.5.301

DENNIS P. CANTWELL, JAMES SWANSON, DANIEL F. CONNOR. Case Study: Adverse Response to Clonidine. https://doi.org/10.1097/00004583-199704000-00017 https://www.jaacap.org/article/S0890-8567(09)62525-9/pdf

Y Li et al, Prevalence and Trends in Diagnosed ADHD Among US Children and Adolescents, 2017-2022, JAMA Network Open (2023). DOI: 10.1001/jamanetworkopen.2023.36872

OJ Storebø, et al. Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – assessment of adverse events in non‐randomised studies. Cochrane Database of Systematic Reviews 2018, Issue 5. Art. No.: CD012069. DOI: 10.1002/14651858.CD012069.pub2.

L Zhang, et al. Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases. JAMA Psychiatry. Nov 2023 doi:10.1001/jamapsychiatry.2023.4294

LM Ortiz, et al. Psychostimulants prescribed to children for ADHD following distal radius fractures significantly reduce bone density as a function of duration. Journal of Pediatric Orthopaedics B (2023). DOI: 10.1097/BPB.0000000000001125

JC Vázquez et al. Effects of Caffeine Consumption on Attention Deficit Hyperactivity Disorder (ADHD) Treatment: A Systematic Review of Animal Studies. Nutrients (2022). DOI: 10.3390/nu14040739

A Nair, et al. A functional logic for neurotransmitter corelease in the cholinergic forebrain pathway. Proceedings of the National Academy of Sciences (2023). DOI: 10.1073/pnas.2218830120