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Tens of millions of American adults wonder if they have ADHD. People seem to be more distracted, forgetful, and less willing to wait their turn. At times it seems that everyone has ADHD.

ADHD experts have written numerous informative books, describing ADHD symptoms and treatments. But they scrupulously draw a line between those with ADHD and others who merely have “everyday” lapses in attention, concentration, or working memory. Similarly, several authors have described how our information society is impairing our capacities for sustained concentration and thoughtful reflection. But they differentiate this fallout from our internet lives as being distinct from clinical mental health conditions like ADHD.

The concept of the ADHD spectrum helps elucidate connections between clinical ADHD and ADHD-symptoms induced by overexposure to our electronic devices. Awareness of the ADHD spectrum also prompted me to write the book ADHD World, which seeks to combat three myths:

• You either have ADHD, or you don’t.

• ADHD is simply a genetic condition.

• The only effective ADHD treatment is stimulant medication.

ADHD World is for those who have observed changes in their own thought patterns and behaviors, or noticed them in others. ADHD World helps us understand why we are seeing more symptoms of ADHD across our society, and what we can do about it.

The ADHD spectrum

Mental health professionals diagnose ADHD when an individual displays a certain number of symptoms of inattention, impulsivity, or hyperactivity, which must be excessive compared to one’s peer group, cause distress or impairment, have arisen in childhood and persisted for many months, and not be attributable to other conditions. We have no brain scans, blood markers, or psychological tests that confirm an ADHD diagnosis.

Current diagnostic frameworks cast ADHD as a categorical decision — someone either fulfills the criteria or doesn’t. Yet ample evidence reveals that either taken singly or collectively, an individual’s symptoms of ADHD exist along a spectrum within the population. It’s not all or none; people can demonstrate no, mild, intermediate, or extreme degrees of ADHD-like behavior.

Furthermore, we know that many individuals don’t remain fixed at one point along this ADHD spectrum, but can slide back and forth towards having more or less intense ADHD behavior. Many individuals who meet criteria for subthreshold ADHD at one point in their life have full clinical ADHD at another time. Many individuals diagnosed with clinical ADHD will at some later date only display subthreshold ADHD or an even milder degree of symptoms.

Rather than just being a collection of symptoms, many researchers, clinicians, and those with ADHD consider it a condition in which individuals experience atypical activity and performance of their executive functions. Executive functions are how the brain manages, processes and utilizes information, and can include attention, concentration, prioritization and organization of tasks, working memory, time management, impulse control, emotional regulation, and other functions.

For characteristics existing on a spectrum of intensity or severity, any line dividing the spectrum into what is “normal” and what is “not” involves some degree of arbitrariness. We can use statistics to demonstrate that most people who display more than a certain number or intensity of symptoms will have negative outcomes in life, but even so, we will still misclassify some individuals on either side of the line. In part, this is because ADHD is always only one aspect of any individual. Each of us possesses additional strengths and traits that shape how we function in the world, and our past and present environment also influence us.

Rising rates

I started working with adults with ADHD more than thirty years ago, right when we began to appreciate that this wasn’t just a condition that disappeared at the end of childhood. Changes in awareness of ADHD in adults, by both mental health professionals and the wider public, have contributed to rising rates of diagnosis.

Also, in 2013 the official definition of ADHD was broadened, so that symptoms only needed to arise before age 12, rather than 7, and adults needed only 5, not 6, symptoms to qualify. Loosening the criteria for diagnosing adult ADHD may also account for increased rates of diagnosis. But neither the timing of greater awareness of ADHD, nor of the slight change in how it is defined, aligns particularly well with recent surges in ADHD diagnosis and treatment, and thus are at best two partial explanations for these increases.

Others have tried to dismiss the recent rise in ADHD diagnoses as being due to mistakes. Depression, anxiety, certain drug addictions, and even dementia can resemble some aspects of ADHD. But many recently diagnosed individuals don’t display features of other mental health conditions, and multiple studies indicate that we are continuing to substantially under diagnose ADHD, missing cases when it is present, rather than over diagnosing it.

One part of the reluctance to accept that recent increases in ADHD are genuine comes from those who cling to the genetic basis of ADHD. Because all of its symptoms are behaviors exhibited at times by almost every human, ADHD is often dismissed as a fabrication. Many in the ADHD field rely on the evidence that genetics contribute strongly to who develops ADHD as proof that it is a legitimate, brain-based condition.

The strong genetic contribution to ADHD has been widely replicated by numerous studies conducted with different methodologies and in different populations. But a strong genetic influence doesn’t rule out environmental factors playing a role. Indeed, nature and nurture always work together to generate human behaviors.

Environment matters

Indeed, clinical lore has repeatedly acknowledged that those with ADHD often show up initially for evaluation and treatment at times of transition. Individuals with ADHD are likely to seek help when their symptoms cause greater impairment because a new role places increased demands on performance, or reduces supportive structures, or both. Examples of such times of transition include starting high school, enrolling in college, beginning a new job, or entering retirement.

The COVID epidemic represents another example of an environmental change that worsened ADHD symptoms and pushed many people further along the ADHD spectrum. Interestingly, many mental health pundits predicted at the beginning of the pandemic that sequestering people at home, conducting work in isolation from colleagues and within living spaces, and increased economic pressures would lead to more depression, anxiety, substance abuse, and domestic violence.

Their forecasts failed to include an increase in ADHD despite the fact that for many, the demand to individually manage one’s professional and personal space and time in an era of social upheaval was an ideal recipe for intensifying ADHD symptoms. An increase in ADHD should have been a predictable outcome of COVID disruptions to our lives.

The ADHD exposome

One of the most widely recognized factors degrading our attention is our immersion in the internet world. Big Tech has engineered software and hardware to hijack our attention and sell it as a commodity.

But just as the label ADHD directs undue focus on problems with attention, neglecting the much broader range of executive functions affected by ADHD, so too the phrase the “attention economy” channels too much focus on attention as the primary victim of over absorption with our always-accessible computer devices. Our excessive reliance on social media and the internet undermines not just sustained concentration but also our ability to plan, prioritize, control impulses, and regulate emotions.

Unfortunately, our obsession with the online world is not the only factor propelling our brains further along the ADHD spectrum. The ADHD exposome is defined as those factors beyond genetics that influence the development of ADHD symptoms.

The exposome includes aspects of our lifestyles and habits — how chronic sleep deprivation, poor nutrition, and lack of exercise can generate or worsen ADHD symptoms. The exposome also includes physical aspects of our world, such as contamination with plastics and lead; lingering effects of infections (like long COVID); or increased temperatures. All of these factors can rewire or interfere with our prefrontal cortices where much of the neurocircuitry of our executive functions is located. Even social factors, like pervasive emotional trauma, authoritarian parenting styles, and loneliness, appear capable of promoting ADHD symptoms.

None of these environmental factors have clear and simple effects on our brains — there are a multitude of feedback loops and interactions. For instance, chronic sleep deprivation worsens ADHD symptoms, but ADHD itself leads to sleep disruptions in a number of ways. And sleep deprivation is associated with poorer diets, less exercise, and poorer performance at work and school, which themselves can exacerbate ADHD symptoms.

Treatment

Although stimulant medications can powerfully reduce ADHD symptoms, they also can cause serious side effects, including psychotic responses and triggering addiction. Fortunately, a number of other medications without those risks can also measurably help with ADHD. Furthermore, a number of therapy interventions, including family and individual approaches that reshape communication, thoughts, and behaviors, can improve daily functioning for those with ADHD. Numerous other approaches to changing the brain, from neurofeedback, to electrical stimulation of brain circuits, to acoustic interventions, also show promise for reducing ADHD symptoms.

So far, many of the approaches, both medication and otherwise, that help with clinical ADHD also seem effective in diminishing ADHD symptoms that appear to have a strong environmental influence. For example, both low dose stimulants, or guanfacine, a non-stimulant medication, reduce ADHD symptoms arising from brain trauma or long COVID.

Summary

We diagnose conditions in order to understand them, to provide general predictions of the future, and to guide in the selection of specific treatments. Identifying that in many ways our modern world is pushing many of our brains along the ADHD spectrum serves similar purposes: it helps us become aware of what is going on, suggests possible outcomes if we don’t change anything, and offers remedies if we want to push our society in a less-ADHD direction.

The intent is not to eradicate all symptoms of ADHD. ADHD contributes to making some individuals particularly curious, creative, venturesome and resilient.

We’ve been busy creating a world that promotes ADHD symptoms, but we haven’t really been paying attention. We should be asking ourselves whether this is really the world that we want to reside in. We need to know that cell phone use is not the only force pushing us along the ADHD spectrum, rather, a myriad of other factors are at play.

We should also be aware that attention is not the only domain of brain function adversely impacted by computers and other parts of the ADHD exposome — our ability to plan, organize, control our impulses, and regulate our emotions are also being altered. Thankfully, because of the thousands of research articles on clinical ADHD, and the successful treatment of millions of individuals with ADHD, we already have some good ideas regarding what can help people at less intense segments of the ADHD spectrum, and what aspects of our environment to work on improving.

These ideas are explored in greater depth in ADHD World: Why We’re Losing Focus and What to Do About It.

More people are using nitrous oxide, or laughing gas, to become intoxicated, with increasing numbers of people being injured, or even dying, in the process. A Northern California congressman has introduced the first federal legislation to restrict consumer access to nitrous oxide.

At the same time, a growing body of evidence demonstrates that nitrous oxide can quickly alleviate major depression — without some of the potential complications posed by ketamine.

How our government regulates access to nitrous oxide is no laughing matter — potentially the mental health of millions will be impacted.

Public health measures that balance individual and societal risks and benefits always involve more than science because they necessarily incorporate values and priorities. But understanding the facts about nitrous oxide is essential, because good public policy will not violate the truth.

Nitrous oxide is a gas, gas, gas

In biology class you were probably taught that humans and other animals breathe in oxygen and breathe out carbon dioxide. But that’s not quite right. Earth’s air is mostly nitrogen, so when it’s dark outside most of what you’re breathing in and out is nitrogen — and in the morning you don’t suddenly start breathing daytrogen.

Our air is 78% nitrogen (N2) gas, which is largely stable and inert. It’s also 21% oxygen (O2), which supports life and is far more reactive than nitrogen, contributing to rust and a number of other oxidative processes. The other 1% of our air is mostly argon, with dozens of other gases existing only in trace amounts.

The dramatic rise in carbon dioxide (CO2) and other greenhouse gases in recent decades is real, even if numerically tiny. CO2 levels are measured in parts per million. Yet very small changes in the amount of these greenhouse gases produce profound changes in how our atmosphere traps heat, with major consequences for the climate and for human and other life.

Another of those greenhouse gases is nitrous oxide (N2O), which is a natural component of the nitrogen cycle — how nitrogen moves from an inert gas in the air to an important chemical component of all living things. N2O is produced naturally by decaying vegetation. But levels of N2O have increased 40% in the last four decades, to current levels of about 33 parts per million, because of anthropogenic (manmade) actions. This increase in N2O has come primarily from the extensive use of nitrogen-based fertilizers, as well as from massive emissions from the manure pits of modern factory farming.

Nitrous oxide is considered the third most important greenhouse gas, after CO2 and methane. Although CO2 levels are about 15 times higher than N2O, and CO2 lasts longer in the upper atmosphere, N2O traps heat 200–300 times more efficiently. And unlike CO2, N2O also depletes the protective ozone layer.

Nitrous oxide is a clear, relatively inert gas, somewhat denser than air. It should not be confused with either nitric oxide (NO) or nitrogen dioxide (NO2).

NO plays a role in expanding blood vessels in humans. This vasodilator action is how Viagra works to flood erectile tissues with blood. NO also acts in the brain as a neurotransmitter. Motor vehicle exhaust is an important source of NO, which is a clear, highly reactive and combustible gas.

NO2 is produced primarily by motor vehicles and is a major component of smog. It’s a reddish brown, highly reactive, and toxic gas.

It’s a laugh

Joseph Priestley, the British chemist who discovered oxygen and was one of the founders of the Unitarian Church, was the first to synthesize nitrous oxide in 1772.

A generation later, another famous English chemist, Humphry Davy (who discovered sodium, barium, chlorine and other elements) was researching the possible medical benefits of various gases. In 1799, Davy found that nitrous oxide made him feel somewhat tipsy and giggly, and named it laughing gas. He also discovered that N2O has anesthetic properties.

Brilliant and good-looking, Davy, who was only 20 at the time, delivered popular lectures that were widely attended. Before the end of 1799, people were having laughing gas parties in England.

Nitrous oxide was the first anesthetic used in surgical and dental procedures. However, in the 1840’s both ether and chloroform began to replace N2O because they were both more powerful in reducing pain as well as being more sedating. It’s easier for surgeons to operate on bodies that aren’t squirming around.

Nitrous oxide never disappeared from use as an anesthetic. It is still used today in clinics, particularly during labor and delivery and for some cardiac procedures, often in combination with other anesthetics. Nitrous oxide still provides a faster onset to anesthesia than many of the alternatives, and also helps reduce anxiety.

The mainstay of medical nitrous oxide use is in dentistry. Most commonly, it is used in conjunction with an injected, more potent, local pain reliever, like lidocaine. Dentists like to use nitrous oxide because of its:

• safety

• rapid onset

• quick termination of action

• low cost

• ability to reduce anxiety

• minimal side effects or hangover.

Many people fear needles, so the use of inhaled nitrous oxide allows for needles to be avoided, or at least delayed until after the individual is no longer conscious.

Some people do have nausea and headaches from nitrous oxide, but this is much less common than in Davy’s day, when people inhaled pure (100%) N2O from little silken balloons. Today, nitrous oxide in dental or medical settings is usually inhaled at 25% or 50%, with the remaining fraction of the mixture being oxygen. This increases the safety as well as minimizing side effects, which tend to be dose dependent.

Chefs have also found uses for nitrous oxide, particularly as a propellant for whipped cream. It dissolves well in fat, allowing cream to be whipped up to four times its volume, in contrast to only doubling the volume that is achieved by whipping in air. However, N2O- whipped cream is not as stable as air-whipped, and will collapse within a few hours, unless chemical stabilizers are added.

Nitrous oxide can also be used to make other culinary foams. It can rapidly infuse oils and alcohols with herbal, fruit, spice, and other flavors that would usually take weeks or months of soaking for the essences to permeate.

Laughter is the best medicine

Research into N2O as a mental health treatment was inspired by the rapid adoption of ketamine for depression. Conventional antidepressants take many days to a few weeks before they bring relief, whereas ketamine works within minutes to hours. (Many sources mistakenly consider ketamine to be the first rapid-acting antidepressant, but more than fifty years of research document that stimulants can also alleviate depression within minutes.) Within a few years of realizing the antidepressant action of ketamine, hundreds of clinics opened across the US to provide intravenous ketamine for depression, chronic pain, and other ailments.

Most of the early research on ketamine strongly implicated its blockade of NMDA glutamate receptors for its antidepressant action. But pharmacologists failed to show that other NMDA blockers alleviated depression. More recently, a number of studies indicate that the ability of ketamine to activate mu-opioid receptors, in combination with its NMDA-blocking action, appears critical for its antidepressant success.

Nitrous oxide has a similar neurochemical profile to ketamine, possessing both NMDA-blockade and mu-opioid action. However, N2O does not provoke either the immediate extreme fluctuations in blood pressure, or the long term bladder problems that can be side effects of ketamine. Furthermore, N2O’s dissociative and hallucinogenic effects appear to be milder and more likely to be positive experiences compared to those from ketamine. Whether the abuse and addiction potential of N2O is lower than that for ketamine remains an open question.

More than two dozen studies have found that nitrous oxide can successfully treat depression. However, of those studies, only seven were gold-standard randomized controlled trials, and these included less than 300 adult subjects. Within two hours of a 30–60 minute session with either 25% or 50% N2O, depressive symptoms were significantly reduced, and stayed low for at least 24 hours.

A week after treatment, average scores on depression rating scales were trending back up. But additional studies, delivering N2O weekly or twice weekly treatments, can maintain an antidepressant effect.

50% N2O appears to work better than 25% for depression, but more data is needed to confirm this dosage effect. Like ketamine, nitrous oxide appears to be a potent antidepressant. Some of the published studies included individuals selected for being treatment resistant, having failed at least 8 (!) previous antidepressants, making the success of N2O all the more impressive. Also of note, in these clinical trials side effects tended to be minimal and transient.

One weakness of the available studies is that the immediate effects of inhaling nitrous oxide are distinctive enough that most patients know what they are receiving. This can create expectation effects if subjects sense they are receiving an active treatment rather than a placebo.

Laughing gas clinics?

Is nitrous oxide poised to replicate the success of ketamine, with clinics sprouting up across the country? After all, it seems to be safer, is at least as rapid in onset, and appears to be nearly as effective as ketamine for the treatment of depression.

Some naysayers have pointed out that fancy equipment is needed to administer N2O in medical settings. But early ketamine clinics required placement of an intravenous line, as well as blood pressure monitoring. Nowadays, some ketamine clinics continue to use IV treatment, while others employ easier intramuscular or subcutaneous injections, and some use oral pills or nasal inhalers. Monitoring of cardiac status is still recommended.

The critics also seem to ignore that millions of individuals are already self-administering N2O without supervision, and that small canisters of the gas are readily available. Furthermore, there is already a nationwide network of thousands of medical nitrous oxide delivery sites already available: dental clinics.

From what I’ve seen, many dentists are entrepreneurs willing to extend their practices into lucrative side ventures. Fifty years ago, most dentists’ work consisted of filling cavities, but when fluoridated water and toothpaste vastly decreased the number of cavities, they found other ways to expand their businesses. The per capita number of dentists in the US has stayed remarkably constant for decades.

I can imagine dentists partnering with psychiatrists, nurse practitioners, or even psychologists to utilize their N2O-delivery devices for treating depression. I think it’s even plausible for some dentists to expand their scope of practice from dental to mental health. Don’t laugh, but maybe someday you’ll hear your dentist asking: “Feeling down in the mouth? It’s all in your head isn’t it? How about some laughing gas?”

If you think that’s far-fetched, it’s not much more absurd than the fact that the vast majority of the first generation ketamine clinics were staffed by anesthesiologists — professionals whose primary medical interactions were with unconscious individuals. Not many of them had mental health expertise.

Government regulations that try to prevent nitrous oxide abuse might pose a barrier to laughing gas depression treatment centers. On the other hand, ketamine clinics have thrived in a regulatory gray zone. To this day, the only FDA-approved ketamine treatment for depression is the esketamine nasal inhaler, which doctors are only permitted to use in approved clinics. That hasn’t prevented widespread home use of both ketamine pills and nasal inhalers, or the off-label use of ketamine injections in clinics.

The downside

About 5% of Americans acknowledge having tried nitrous oxide for recreational purposes. In other surveys, as many as 20% of individuals have tried it at least once. In Britain, N2O is the third most common substance used illicitly, after marijuana and cocaine. Use has been surging over the last decade in Europe, the Americas, and parts of Asia.

Nitrous oxide is attractive as an intoxicant because it is:

• inexpensive

• accessible without associating with dangerous individuals

• works quickly

• is usually a positive experience

• ends quickly

• seldom produces side effects or withdrawal

• is perceived as harmless by most users.

In the US, poison control center calls related to nitrous oxide have increased 5 to 6 fold compared to the years prior to 2015, with about 10% of cases involving intensive care treatment. Deaths have also increased, with more than 120 per year every year since 2018.

Nerve damage, which can be serious, is the most common serious side effect from nitrous oxide. About fifteen years ago, I worked with a Scandinavian woman in her early thirties who had numbness and tingling in her legs and walked with a limp because of nitrous oxide. She had started inhaling small nitrous canisters at parties in her native country a few years before I first saw her.

Her permanent neurologic problems, unresponsive to treatment, contributed to her depression. She understood that N2O was causing her neurological problems, but it also gave her temporary respite from her depression, which was unresponsive to conventional antidepressants or vitamin supplements. She struggled with abstaining from nitrous oxide use, which was both self-medication and self-poisoning. Eventually she moved back to her home country.

The primary route for nitrous oxide to cause nerve damage is through Vitamin B12 depletion. N2O oxidizes cobalt, which inactivates Vitamin B12. This leads to disruption of methylation pathways, which causes degradation of the insulating myelin sheaths around the long axonal projections of neurons. Researchers have documented both spinal cord and peripheral nerve lesions from N2O use, which is usually associated with long-term and excessive nitrous oxide inhalation by vulnerable individuals.

The whipped cream canisters commonly misused to achieve intoxication contain 100% nitrous oxide. This produces a risk of oxygen deprivation, which can also cause nerve damage, or if extensive enough, death. Several nitrous oxide-related deaths have been intentional suicides by asphyxiation.

Because more than 99% of the nitrous oxide someone inhales is present in what they exhale, this also creates an opportunity for second-hand intoxication. Because individuals usually only inhale small volumes of N2O, secondhand toxicity only becomes an issue in small rooms with poor ventilation or with numerous users. Nitrous oxide is more dense than room air, so its levels become more concentrated near the floor.

The laugh police

Concern about increasing rates of nitrous oxide recreational use, and harm from it, is driving current proposed legislation. In March 2026, Northern California representative Kevin Mullin introduced the first federal law that would restrict and criminalize recreational / consumer use of nitrous oxide, while preserving exemptions for food processing, medical and dental anesthesia, and industrial uses. The act is an attempt to prevent nitrous oxide use from becoming a bigger public health problem in the US.

Currently, the FDA regulates nitrous oxide and forbids the marketing or selling N₂O for human consumption outside of prescribed medical or culinary uses. Several states have more rigid restrictions. But these are quite widely flaunted.

For years, the “whippet”, an 8 gm, 3-inch long metal cartridge intended for a single-use whipped cream canister, has been the major vehicle for self-dosing with nitrous oxide. However, in recent years companies have added flavorings and boosted the size of canisters in blatant attempts to target group use among young recreational users.

When I checked to see how easy it would be to obtain nitrous oxide, my internet search immediately pulled up several links to companies selling 200 gm canisters (25 times a single-use whippet!) of nitrous oxide flavored with “wondrous watermelon”, “strawberry sensation”, “fresh apple” and “blueberry punch”. The websites provide profuse disclaimers that they’re not marketing for recreational use. However, although there are plenty of fetishes out there that I know little about, I doubt that many caterers face demands from customers seeking bathtubs full of fruit-flavored whipped cream.

Public health requires balancing the rights and desires of individuals against the risks and costs to society. We don’t need to be whipped into a frenzy about the risks of nitrous oxide, but the public should be aware that individuals are dying from its use. Nitrous oxide has appropriate and valuable medical uses, which may soon expand from anesthesia into depression treatment.

Although N2O is generally safe, users should be aware of its potential dangers, and companies should be blocked from marketing to vulnerable teens and others with a high risk for abusing this gas. If you have strong feelings for or against the pending federal legislation, let your representative know.

If I’m not promoting nuance, I’m probably creating new angst.

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Two months ago I wrote about a research article that presented one of the most exciting discoveries that I have seen in my thirty plus years as a psychiatrist and neuroscientist. Sichuan University psychiatrist Nanyang Pan and collaborators in the US and Australia found biomarkers associated with three discrete, non-overlapping varieties of ADHD. For the first time in psychiatry, we had a laboratory test that could definitively identify a specific mental health condition.

The research garnered some attention in the general media as well as in the mental health world — less than was warranted, given the importance and quality of the work. But much of the commentary was somewhat smug and self congratulatory, claiming that the research affirmed the new categorization of ADHD biotypes “mirrored” the subtypes already identified by our current symptom-based diagnostic system.

Nothing could be further from the truth.

The three biotypes of ADHD identified by Pan’s team don’t align at all with conventional subtypes of ADHD. Adoption of the biotypes uncovered by Pan’s research would require completely throwing out our old diagnostic categories. If such findings can be extended to other psychiatric diagnoses, we’re facing a complete reorganization of what we thought we knew.

Much of the mental health field seems to be ignoring this potential cataclysm, and pretending that we can continue with business as usual. Psychiatry is missing the boat. But making any significant progress in the treatment of mental health conditions will require us to adjust to the new realities.

(Bio)mark my words

Researchers have long sought biological markers for psychiatric conditions — both to legitimize that the conditions they treat actually exist, and to more precisely match effective treatments to the underlying origins of these conditions. Despite innovative approaches and years of research, genetic, brain imaging, blood biochemical assays have failed to deliver.

For many conditions, researchers have found variables which on average differ between those with a mental health condition and those without. The hippocampus of those with chronic depression tends to be smaller than those who haven’t been depressed. An unusual abundance and activity of dopamine transporters is found in the forebrains of individuals with ADHD. Genetic analysis can identify who is at increased risk of developing schizophrenia.

But because the range of measurements varies so widely both among those who have a condition, and in the general population, there is considerable overlap between the two groups, and none of these potential biomarkers can be used to determine which group an individual belongs to.

With a true biomarker, the results of a test, whether a genetic analysis, the level of a hormone or neurotransmitter in the blood, or a pattern of neural wiring or activation in the brain, confirm that the individual has the condition.

Many researchers and clinicians have felt that progress in developing more effective mental health treatments has been stymied because what we think are conditions don’t truly reflect underlying distinct biological processes. What we call depression is probably a collection of different biologic conditions, and patients arrive at the final endpoint of symptomatic depression after traveling very different trajectories. The same is likely true with anxiety, schizophrenia, substance abuse, ADHD, and most of our psychiatric conditions.

There are also some contrarians who insist that we will never find biomarkers for mental health conditions because they are purely social constructs.

Uncovering underlying brain-based substrates for mental health conditions (if they truly exist) would likely help us devise treatments that specifically address anomalies of biochemistry, connectivity, or neural activity. But it could also invalidate hundreds of thousands of research papers based on conditions that don’t truly exist.

What we thought we knew about ADHD

For several decades, the official Diagnostic and Statistical Manual (DSM) categorization of mental health conditions has been based on symptom profiles — collections of behaviors, thought patterns, and emotional displays that characterize each condition. The diagnosis of ADHD is based on nine DSM symptoms of inattentive behavior and nine DSM symptoms of hyperactive / impulsive behavior. These symptoms have to be pervasive, excessive for one’s age and social group, and produce either significant dysfunction or distress.

For adults, only five symptoms need to be present. If these symptoms are primarily inattentive, the individual has inattentive ADHD, if they are primarily hyperactive or impulsive, they have hyperactive/impulsive ADHD (which tends to be rare) or if they have substantive symptoms from both groups they are deemed to have combined type ADHD.

The DSM criteria were developed initially for children with ADHD and then extended to address the condition in adulthood. The DSM fails to include a number of symptoms that many researchers had identified as central to ADHD, including altered time perception and poor time management, and emotional dysregulation, hyperfocus, and sleep disturbances.

Biotypes of ADHD

Pan’s research looked at patterns in the connectivity between hundreds of different areas in the brain, in hundreds of children. They found four distinct, non-overlapping, patterns of neural connectivity. One pattern corresponded to the children in their study without ADHD. Three distinct patterns of uncommon wiring were found in the brains of children with ADHD.

This research was conducted at several different sites, and then was replicated with subjects from completely different locations, strengthening the validity of the findings. In both the study and replication, each of the three ADHD biotypes made up roughly one third of the individuals with ADHD.

Measurements of anomalous wiring patterns required not only complex MRI recordings of the brain, but also sophisticated number crunching techniques only possible with modern computers. The computer algorithms looked at patterns of brain connectivity without initial assumptions about whether these would cluster into coherent groups. More study details can be found in my previous article.

The researchers labeled the three ADHD brain wiring patterns biotypes1, 2, and 3. Symptoms of emotional volatility, along with severe symptoms of inattention and hyperactivity were found in biotype1 individuals. Individuals in biotype2 scored highly on hyperactive symptom scales of ADHD, and biotype3 individuals had very high inattentive scores.

On the surface, that looks like a pretty good match for the current DSM division into combined, hyperactive, and inattentive types of ADHD. A summary from the American Psychiatric Association daily electronic newsletter even noted that the hyperactive and inattentive “categories map neatly onto the way ADHD is currently diagnosed.

They don’t line up

Pan’s article, however, clearly shows that the biotypes they uncovered do not align with DSM subtypes.

For one thing, individuals in their biotype2 didn’t just have high hyperactivity/impulsivity, they also displayed substantial symptoms of inattention. And those in biotype3 didn’t just have high inattention, they also displayed substantial hyperactivity/impulsivity.

Helpfully, Pan’s article actually provides a breakdown, for each DSM subtype, which biotype they fit into:

Of those with DSM inattentive ADHD, 25% were biotype1, 45% biotype2, 30% biotype3

Of those with combined type ADHD, 40% were biotype1, 40% biotype2, 20% biotype3

Of the tiny group of hyperactive ADHD, 33% were biotype2 and 66% were biotype3

There is virtually no correspondence between biotypes and DSM categories, except for the unfortunate choice of occasionally using the labels “emotional/severe”, hyperactive, and inattentive for biotypes1,2,3 respectively. The biotype labels aren’t even fun house mirrors of DSM — the patients don’t align at all.

The diagram below may help make this clear. On the top line are the group distributions found in Pan’s study. The second line is what would be expected if the three biotypes actually aligned with the three DSM categories.

One of the revolutionizing aspects of this research is that it completely repudiates the DSM criteria for ADHD subtypes. The unfortunate occasional reference by Pan et al. in calling biotype2 “hyperactive” and biotype3 “inattentive” confused some readers into thinking that these biotypes corresponded to DSM categories. They don’t.

Rethinking

Pan’s study was restricted to finding biomarkers for subtypes of ADHD. Similar projects by other teams are likely to revise the boundaries of ADHD itself. New biomarkers will probably revise whom we include within the diagnoses of ADHD, and whom we exclude because they really have a different condition that shares some symptoms. These advances are unlikely to be limited to just ADHD, but will extend to all of our current mental health conditions.

The fact that many of our current mental health diagnoses and subtypes don’t reflect true underlying conditions presents obstacles for research into figuring out how our brains work and what is occurring when they work in atypical ways.

A recent study on local sleep in ADHD provides an example. Local sleep refers to the existence of small clusters of cells going offline and inactive during the daytime in an otherwise awake and alert individual. Local sleep occurs more frequently in those with ADHD than in typical brains, and appears to contribute to lapses in attention and other errors in other cognitive tasks.

The study explored whether local sleep was more common in different subtypes of ADHD. They only found minor differences, and this was after cherry-picking different brain regions from among different ADHD subtypes.

These results aren’t surprising if DSM subtypes and diagnoses don’t really reflect biological differences. Presumably, a replication of the local sleep study on individuals classified according to the genuine ADHD biotypes uncovered by Pan’s group might reveal more substantial differences in local sleep.

Keep it simple

One drawback of the brain-wiring-pattern ADHD biotypes uncovered by Pan is that they don’t have immediate clinical relevance. Most mental health clinics have neither the MRI apparatus capable of mapping brain connections at this precise level of detail, nor the sophisticated software to ensure patterns of connectivity and determine how they differ from those of an average brain of the same age.

If Pan’s ADHD biotypes pan out, meaning they are replicated and found to correspond to groups of individuals that share biological features relevant to a mental health condition, then researchers are likely to search for, and find, other, more accessible biomarkers for these conditions. The development of blood tests or simple brain imaging procedures to identify who has a specific mental health condition would greatly advance research and the treatment of individuals.

This could introduce a new problem: what do we do if the biomarkers for a condition don’t perfectly align? That’s already the situation we face with gender. Although for many individuals the categories “male” and “female” make sense and are consistent at the level of chromosomes, gene expression, hormonal levels, genitalia anatomy, and internal sense of self, for other individuals there are discrepancies between some of these facets of gender.

While some advocate that the existence of such discrepancies means that we should simply abandon the concept of gender altogether, more often researchers and involved individuals support muddling along and acknowledging that many people don’t fit simply or entirely into our categories of male and female.
We won’t know how often misalignment of biomarkers will occur with mental health conditions until we uncover such biomarkers.

Waving the ship goodbye

It appears that many mental health experts have yet to fully grapple with the existence of psychiatric biomarkers. There seems to be a strong urge to ignore how clearly Pan’s ADHD biotypes refute our symptom based categorization.

Part of clinging to the past may just be the perpetuation of old habits. Just as individuals may intellectually know and accept that a friend or family member has transitioned in their gender, they may struggle, at least occasionally, with the proper pronouns for that person.

But I think that the resistance to rejecting our old symptom based system of diagnosis goes considerably deeper than retaining linguistic habits. Rejecting the old system means suspending belief in decades of clinical and research findings about mental health conditions. If our new categories don’t align with the old DSM criteria, that would indicate that many individuals really didn’t fit into the little diagnostic boxes that we had thoughtfully, neatly, and carefully placed them in.

Some would say this would render all previous mental health research obsolete and worthless. At best, it will require a lot of thought and cognitive contortion to salvage useful knowledge gleaned from somewhat, or sometimes drastically different diagnostic labels.

Mental health workers should be particularly familiar with how hard it is for people to let go of viewing the world in ways they have been trained to see, and which they have practiced for years. So much of what we do in the field is helping patients reprogram themselves from restrictive, harmful, and inaccurate conceptions of themselves, their worlds, and their relationships.

So even though the early evidence isn’t reassuring, I think that in the long run, the mental health field will be able to adopt a biomarker approach, and let go of previous notions about the boundaries of our psychiatric conditions. The ship is already sailing.

If I’m not promoting nuance, I’m probably creating new angst.

ADHD runs in families; genetics play a large role in determining who develops ADHD. But as with every facet of human behavior, nature and nurture are always interacting. Our environments shape us.

The ADHD exposome is defined as the total set of non-genetic exposures from before birth until death that influence the appearance and severity of ADHD symptoms. This includes environmental factors, experiences, lifestyles and habits. Where we live and how we act affect where we are situated along the ADHD spectrum; the exposome can either lessen or intensify ADHD symptoms.

For ADHD and most other human conditions, genetics have been studied more extensively than environmental factors. But given that we are likely to have more choice and control over our environmental exposures than over our genetics, it makes sense for each of us to learn more about which features of our exposome may be playing a significant role in promoting or discouraging ADHD. As I described in a recent article on the ADHD spectrum, the exposome can push or pull people from clinical ADHD to subthreshold ADHD to having just a few or occasional ADHD symptoms.

Starting with genes

Twin and adoption studies confirm that at a population level, genes play the single largest role in determining who develops ADHD. Multiple studies have found the heritability of ADHD to be in the 70–80% range.

Early researchers hoped to find genes, such as those for dopamine receptors or transporters, that explained most of the genetic contribution to ADHD. But such “candidate genes” seem to play a determinative role in causing ADHD within only a few families. Much more often, hundreds of genes each contribute a very tiny bit to shape who is likely to develop ADHD.

In addition to gene variants playing a role in increasing the likelihood of who develops ADHD, mitochondrial DNA variants, the number of copies of sections of the genome, and unidentified genetic factors contribute to the heritable component of ADHD.

Using modern techniques we can scan all of a person’s DNA to develop genomic risk scores for the likelihood of developing ADHD. But even whole genome risk scores only provide approximate information. The quarter of the population with the highest ADHD genetic risk scores is only slightly — not even twice as likely — to have ADHD as the quarter with the lowest scores.

If the genetics of ADHD sound complicated, that’s nothing compared to the exposome which has many more constituent parts, many of which are more difficult to study.

One reflection of challenges to studying the exposome can be derived from a search of PubMed, which categorizes medical research studies. PubMed lists more than two million published articles about the genome and only 1/500th of that, or about four thousand, for the exposome. Even while acknowledging that “exposome” is a more recent term than “genome”, it’s still apparent that we’ve only just begun to study the exposome. Regarding ADHD specifically, there are similarly hundreds of times as many articles regarding the contribution of the genome compared to the exposome.

An exposome exposé

British pharmacologist and cancer researcher Christopher Wild coined the term exposome in 2005 when he was Director of the International Agency for Research on Cancer. He wanted to emphasize that with any medical condition both nature and nurture contribute; it’s not one or the other. This is especially true regarding human behavior.

Even moving away from the scientific literature to popular searches, Google Trends indicates vastly more frequent searches for the term genome than exposome. Popular searches for exposome have only risen above negligible levels within the last year.

It may be that “exposome” confuses people — they might think that the word refers to someone expostulating about an exposé about which creepy celebrity was exposing themselves. But a larger part of the explanation of the paucity of research on the exposome is that the reductionistic Western scientific approach likes to simplify nature by breaking it down to simple components. The overlapping, confusing, hidden, unrecognized, and self-reinforcing aspects of the exposome resist simple reductionist strategies.

ADHD Spectrum

Currently an ADHD diagnosis is based on having a certain number of symptoms. I believe we’re moving towards a more brain-functional approach, where ADHD will be defined in terms of unusual patterns of brain connectivity and activity affecting what are called executive functions.

Executive functions, which differ from intelligence or knowledge, describe how the brain processes, organizes, and interprets information. They include attention; working memory; response inhibition; prioritization, initiation and completion of tasks; time management; and emotional regulation.

Much of the neural circuitry underpinning executive functions is located in the prefrontal cortex, although other brain areas are also involved. Many of these circuits rely on neural projections from deep within the brain employing dopamine and norepinephrine. Other neurotransmitter systems can influence executive functioning as well.

Brain — World Interactions

One way for many aspects of the exposome to influence ADHD symptoms is through what biologists call epigenetics. The genome consists of the sequence of genes as well as the regions of DNA that don’t directly code for proteins. Epigenetics addresses which genes are turned on or off, which are amplified or restricted. This control over which genes are activated, or expressed, helps determine the specialization of what each type of cell does at each stage of life.

Explanations about an individual’s genetic code, or what we inherit from our parents, often refer to the genome as a blueprint or musical score, and describe epigenetic as how we interpret those plans or that score. However, those analogies ignore that in any cell vast numbers of genes are silenced or ignored, and only a subset gets translated into proteins. A more apt metaphor is a classroom syllabus. The genome represents the source materials, the entire body of literature or research material pertaining to a topic, while epigenetics selects the subset of information that is focused on, or addressed in the course of a semester.

One of the major methods of epigenetic modification consists of affixing methyl chemical groups to segments of the DNA in order to suppress expression of particular areas of the genome. DNA methylation is a common pathway for many parts of the exposome to influence the development of ADHD. A few studies have demonstrated that DNA methylation patterns in infancy can help predict who will display ADHD ten years later.

Timing

At least one study that found DNA methylation in infancy predicted later ADHD failed to identify methylation patterns at age 10 that were associated with ADHD at that age. This highlights that exposure to factors at different points in time can have different effects on the individual.

For example, lead exposure, Vitamin D deficiency, folate deficiency, extremes of thyroid hormone (low or high), and high testosterone either in utero or early infancy are associated with higher rates of developing ADHD. While exposure to many of these factors can produce damaging effects at any point in one’s life, the impact tends to be smaller, and less strongly associated with the development of ADHD symptoms, when the exposure occurs later in life. The developing brain, when major wiring is being established, is more vulnerable than a brain in which circuits have already become established. Many of these early chemical exposures result in epigenetic methylation patterns that may persist throughout an individual’s life.

Whether or not part of the genome gets methylated also depends upon not just the timing, but the duration of exposure. In general, the longer or more frequently repeated an exposure, the more likely it is to have a lingering effect.

Direct exposome effects on ADHD

Although many aspects of the exposome exert their effects via epigenetic mechanisms, there are often additional, and more direct ways, to generate, maintain, exacerbate, or ameliorate, the symptoms of a condition like ADHD. Direct impairment, interference, or enhancement of neural pathways can influence executive functions and ADHD symptoms.

Currently there is no agreement among experts regarding whether ADHD symptoms that are directly generated are equivalent to ADHD derived from primarily genetic factors. Even if symptoms may appear identical, many consider ADHD resulting from traumatic brain injury at age 47 to be different from ADHD arising in childhood from primarily genetic factors.

The prefrontal cortex, and executive functions, are particularly sensitive to several factors that can inflict direct damage and create ADHD symptoms:

• trauma

• fatigue

• infection

• inflammation

• oxidative damage

The prefrontal cortex, because it takes up a large space, is directly in back of the forehead, and connects to the base of the brain via long pathways, is vulnerable to physical trauma. Much of the damage from blunt trauma to the head comes not from bruising, but from shearing forces which twist the brain and tear at the longest fibers.

The prefrontal cortex is also highly dependent on a special type of neurotransmitter receptor, called the NMDA receptor. Unlike most neurotransmitter systems, NMDA receptors are fatiguable, meaning that their performance begins to deteriorate when used too much in a short period of time. This is why executive functions like resisting impulses or concentrating can become more difficult after sustained effort, whereas one’s neural ability to process visual information or to speak doesn’t start falling apart after hours at these tasks. Decrements in one fatigued executive function can also bleed into the circuitry and performance of adjacent executive functions.

Infection, inflammation, and electrochemical damage to neurons from free radicals can also disrupt the functioning of neural circuits and make ADHD symptoms more intense. Short term depletion of the energy available to neurons is also part of the exposome that can lead to fluctuations in ADHD symptoms.

Exposome organization

A major challenge to studying the exposome for ADHD, or any other condition, is that the term encompasses so many different types of factors that can influence biology and behavior. There is no universally accepted approach to clustering or organizing the various non-genetic forces that constitute the exposome. Even the best of the systems include overlaps and omissions.

Below is one general outline of the exposome. I’ve included links to articles that I’ve written on some of these topics; my articles contain references to the scientific studies documenting these associations.

Chemical exposure

• via air

• via water

• via contact with surfaces

Electromagnetic radiation exposure

• light

• ultraviolet radiation

• infrared radiation

• Xray, radio, and other frequencies

Factors tied to location

• altitude

• urbanicity/ruralness

• greenspace

• climate

• temperature

Lifestyle

• occupation

• education

• finances

• incarceration

• sleep

• diet

• medications and supplements

• substance use and abuse

• exercise

• meditation

Psychological and social

• parenting

• ethnicity / culture

• religion

• trauma

• stress

• loneliness

• internet immersion

Biological factors beyond genetics

• aging

• metabolism

• obesity

• microbiome

• inflammation

• oxidative stress

• hormones

One example of how this organizational framework introduces significant overlap is the attempt to separate out chemical exposure based on method of delivery. Substances like lead and plastics aren’t restricted to one pathway — they can enter our bodies through the air, water, and direct skin contact. Furthermore, where we work and live also affects the likelihood of exposure to higher levels of these contaminants, introducing another source of overlap.

Many analyses of the exposome consider only the visual light part of the electromagnetic spectrum. Light can affect sleep, evoke daytime alertness, and synchronize circadian rhythms thereby directly affecting ADHD symptoms. But human bodies respond to a much broader range of electromagnetic radiation — UV light can cause genetic mutations and increase skin cancer risks, but is also essential for producing Vitamin D. Very little research has explored the potential for non-visual parts of the electromagnetic spectrum to affect ADHD.

Major challenges exist in disentangling the impact of occupation on ADHD. Many in the ADHD community claim that those with the condition perform well in jobs that involve creativity or that require bursts of intense but brief energy, rapid problem solving, and effective crisis management. People with ADHD are unlikely to flourish when a job involves either too much, or too little structure. Because those with ADHD may self-select for certain occupations, it becomes hard to distinguish whether a job has affected ADHD symptoms or whether the presence of ADHD symptoms drove an individual to take a particular job.

I’ve worked with many professionals (doctors, architects, lawyers) who were told that their job title itself refuted the possibility that they could have ADHD. But we know that many people with ADHD may possess other strengths or resources that allow them to thrive in almost any field.

Feedback loops

Feedback loops add further complexity to analysis of the exposome. Sleep deprivation directly replicates the executive dysfunctions characteristic of ADHD. But individuals with ADHD are also more likely to stay up late, display irregular bedtimes and have insufficient and unsatisfactory sleep. Poor sleep pushes individuals further along the ADHD spectrum, and ADHD contributes to further undermining sleep, creating a feedback loop. Numerous other aspects of the exposome demonstrate such feedback loops with ADHD symptoms.

To pump up the complexity another notch, those with poor sleep are also less likely to eat well, exercise sufficiently, and are more likely to feel stressed. All of these factors appear themselves to be separate risk factors for pushing people further along the ADHD spectrum. ADHD feedback loops interact with each other.

Investigations of one feature of the exposome and ADHD usually start by establishing whether a statistical association exists between the factor and the display of ADHD symptoms. We usually need more sophisticated study designs to sort out whether the factor causes ADHD, whether ADHD causes the presence of that factor, or whether some third factor explains the connection between ADHD symptoms and that aspect of the exposome. We have much more evidence for associations between ADHD and various environmental factors than we have clear evidence that aspects of the exposome cause ADHD.

Summary

In my thirty-plus years of working with adults with ADHD the most relevant aspects of the exposome overall appear to be sleep, medications, and other drugs; for most individuals, these have the biggest impact on the severity and presence of ADHD symptoms. However, I’ve seen individuals who have experienced a clinically significant impact from almost every part of the exposome listed above.

The current relevance of understanding which components of the exposome have the biggest impact on developing ADHD are in the realm of public health. For example, we know that minimizing lead or plastics in our environment, or adjusting school or work hours reduces symptoms of ADHD. In a clinical setting, awareness of the exposome might help individuals to change behaviors or avoid aspects of the environment that worsen their ADHD symptoms.

AI and other computer developments are advancing rapidly, but we still appear to be far from the day when an algorithm combines information from our genome and exposome to definitively determine whether an individual has clinically significant ADHD. Whether you think that future time is an improvement over today is probably due to both your genes and your exposome.

Dr. Kruse explores these themes more deeply in his book: ADHD World.

If I’m not promoting nuance, I’m probably creating new angst.

Recently, the FDA cracked down on thyroid hormone derived from natural sources. The FDA for the current administration acted uncharacteristically in that it pushed back against its Make America Healthy Again (MAHA) base and paid attention to scientific findings.

Lots of Americans — more than 23 million — take thyroid hormone. It’s the third most commonly prescribed medication. The majority of that is synthetically manufactured, but some individuals prefer products made from dried out and ground up pig thyroid glands. The FDA will now require sellers of animal-derived thyroid products to obtain a biologics license, which is expected to increase costs and decrease the availability of these animal products.

Although the controversy over biological vs. synthetic thyroid hormone has drawn attention and government intervention, it avoids the bigger issue: lots of people currently taking thyroid hormone probably don’t need to.

A deeper understanding of thyroid deficiency, including ways it can mimic mental health conditions such as depression, anxiety, and ADHD, may help you sort out whether you, or someone you know, actually needs to be taking this hormone.

Decisions about whether to start or continue thyroid hormone should be conducted with your medical team. But many people may want to obtain a second opinion, since many thyroid hormone prescriptions are being filled without a thorough understanding of relative risks and benefits.

Thyroid organization

The human thyroid is a tiny organ, a mere 25 grams (just under an ounce) at the front of the neck, below the Adam’s apple. Although it gets its name from the Greek word for “shield” because of its shape, I side with those who think it looks more like a butterfly, with two big, flat panels connected by a narrow isthmus. However, using “psyche”, the Greek word for butterfly, solely for the thyroid gland apparently stuck in some people’s throat.

The thyroid’s job is to make and release thyroid hormones. The hypothalamus secretes thyroid releasing hormone (TRH) directly to the pituitary gland, which then releases thyroid stimulating hormone (TSH). TSH, also called thyrotropin, travels via the bloodstream, to the thyroid gland, instructing it to make three hormones, thyroxine (T4), triiodothyronine (T3) and calcitonin.

Calcitonin helps regulate the body’s supply of calcium. Thyroid hormones direct a more diverse set of bodily functions, which I’ll list in a moment.

T3 and T4 refer to the number of iodine molecules affixed to the thyroid hormone. The thyroid gland produces four times as much T4 as T3, but many cells in the body can convert T4 to T3 and vice versa. T3 is considered the active form of the hormone, which enters cells and turns on or off certain genes, changing how the cell acts.

Cells throughout the body have thyroid hormone receptors. In the brain, thyroid hormone receptors are concentrated in the prefrontal cortex, hippocampus, and amygdala, which are implicated in controlling the flow of thoughts, emotions, and memories.

T4 lasts about a week in the body, while the half life of T3 is closer to a day. More than 99% of either T4 or T3 circulating in the bloodstream is bound to proteins; the small amount remaining unbound is referred to as “free” T3 or T4. Only free thyroid hormone can enter cells and exert its effects.

Thyroid hormones actions include:

• regulating the rate at which your body burns calories

• adjusting heart rate

• adjusting body temperature

• altering the speed of material through your digestive tract

• organizing brain development

• regulating synapse formation and myelination (how neurons connect, and electrical signals are propagated)

• shaping mood and cognition

• regulating acetylcholine, GABA and other neurotransmitters

• affecting the strength of muscle contraction

• regulating the replacement of skin and bone cells

Too little thyroid hormone

Adequate levels of thyroid hormone are maintained by feedback loops between the thyroid, hypothalamus, and pituitary gland.

Sometimes the thyroid doesn’t produce enough thyroid hormone, a condition called hypothyroidism. When thyroid hormone levels are too low that triggers the hypothalamus to make more TRH and the pituitary gland to make more TSH, in an attempt to compel the thyroid gland to make and release more thyroid hormone.

Elevated blood levels of TSH are the most sensitive and commonly used tool to detect hypothyroidism.

In the US, far and away the most common cause of clinically low thyroid hormone is an autoimmune condition called Hashimoto’s disease. The immune system attacks the thyroid gland, impairing the ability of thyroid cells to make thyroid hormone. Hashimoto’s disease is far more common in women than in men, as well as being more likely with age.

In some parts of the world, iodine deficiency is a major cause of hypothyroidism. Seafood and dairy products usually provide sufficient iodine for most people, and in the US and many other countries salt and bread are fortified with iodine to prevent deficiencies. Although our human ancestors are often depicted hunting mammoths and other large game, for much of human history, fish, not mammoth burgers, have been the major source of dietary animal protein.

Hypothyroidism can also be caused by radiation, surgery, or trauma that physically damages the thyroid gland.

Common symptoms of hypothyroidism include:

• weight gain

• fatigue and sluggishness

• brain fog and problems with alertness

• cold sensitivity

• dry, thickened skin

• coarsened hair

• constipation

• joint pain

The first three of these symptoms are also classic symptoms of depression. This is why thyroid hormone levels are often checked during an evaluation for depression. Although most people who have hypothyroidism will also have some of the other physical symptoms on this list, sometimes the mood and behavioral effects are so prominent that they obscure the other bodily changes, or cause patients to forget to report them to their doctor.

Also, people vary regarding which symptoms of hypothyroidism present first or most prominently. In rare cases, it can be hard to differentiate depression from hypothyroidism just from a physical exam.

The brain fog and confusion of hypothyroidism can also be confused with ADHD or dementia. Again, blood tests checking thyroid hormone can be useful in clarifying a diagnosis.

For individuals with clinical depression unresponsive to traditional medications, supplementing the antidepressants with thyroid hormone has been shown to be effective in alleviating depression for many.

Too little too young

Even though the thyroid is one of the first hormone-secreting glands to develop in the fetus during pregnancy, the fetus is largely dependent on the mother’s thyroid hormone for normal development. Low maternal levels of thyroid hormone impair normal growth.

Infants deprived of sufficient thyroid hormone have stunted height, compromised intellectual functioning, and often a protruding tongue.

Formerly, such individuals were referred to as “cretins” which is now considered a completely pejorative term. However, the word came from a French version of the word for “Christian” referring to individuals growing up in the Alps who suffered iodine and hence thyroid deficiencies. The term was used to remind people that cretins were humans too, even if they had physical and cognitive impairments.

Regardless of the history of “cretin”, I’m doubtful that the word will be restored to respectability any time soon.

Too much thyroid hormone

People can also have too much thyroid hormone. The most common cause is attributed to another autoimmune condition, Grave’s disease. In Grave’s disease the immune system attacks the thyroid gland differently than in Hashimoto’s, so that rather than shutting down the thyroid, it causes it to produce an excess of thyroid hormone.

Overall, hyperthyroidism is substantially less common than hypothyroidism, affecting perhaps 1% of the population. As with hypothyroidism, hyperthyroidism is far more common among women than men.

Typical symptoms of hyperthyroidism entail:

• high levels of restless energy

• feeling overheated

• weight loss

• hair loss

• heart palpitations

• tremor

• diarrhea

• menstrual irregularities

While some of the effects of hyperthyroidism can happen fairly quickly, others become more apparent the longer levels remain high. The signs of hyperthyroidism in the list above are non-specific, meaning that they could occur from a variety of other causes. Two symptoms that are more specific to hyperthyroidism are a goiter, or swelling in the neck, and exophthalmia — a swelling of tissues behind the eyes, causing the eyes to protrude. Goiters can occur from hypo- or hyperthyroidism.

Prolonged hyperthyroidism can produce progressive bone loss, as well as serious arrhythmias and other dangerous heart conditions.

Symptoms of hyperthyroidism overlap with, and can be mistaken for, either anxiety or ADHD. As with hypothyroidism, individuals usually have some physical features of hyperthyroidism that helps distinguish it from these mental health conditions, but blood tests can help clarify whether hyperthyroidism is present when the situation is unclear.

One more cause of hyperthyroidism

Weirdly, increasing evidence indicates that at least in the US, the most common cause of hyperthyroidism is actually hypothyroidism. Millions of individuals appear to be taking too much, or an unnecessary dose of, thyroid hormone.

Recall that earlier I mentioned that elevated TSH is the most sensitive test for hypothyroidism — a sign that your body doesn’t have enough thyroid hormone, and that your pituitary gland is secreting extra TSH to tell the thyroid to work harder. But in many cases, TSH is only somewhat elevated, and thyroid hormone levels are in the normal range. This is called subclinical hypothyroidism.

A meta-analysis by University of Bern physician Martin Feller and colleagues, which included 21 randomized controlled trials totaling over 2000 patients indicated that people with subclinical hypothyroidism don’t benefit from taking supplemental thyroid hormone.

Although the treatment does lower TSH levels back to the “normal” range, for these individuals the “replacement” thyroid hormone provides:

• no benefit in quality of life

• no weight loss

• no improvement in cognitive function

• no change in blood pressure

Only some of the component studies assessed other possible outcomes, but no improvement in fatigue, depression, muscle pain, or strength were detected in the studies measuring these variables.

Part of the problem is that existing standards are probably too rigid in determining what is a high level of TSH. There appear to be normal gender, age, and even seasonal variations in TSH levels that are not accommodated by existing standards.

Subclinical hypothyroidism (high TSH, normal T4/T3) is far more common than clinical hypothyroidism (high TSH, low T4/T3). Huge numbers of these individuals are treated with “replacement” thyroid hormone. Feller’s meta-analysis suggests that those with subclinical hypothyroidism are taking thyroid hormone unnecessarily. Perhaps we need to take these results with a grain of (iodized) salt — they don’t prove that supplemental thyroid hormone is useless for every individual with subclinical hypothyroidism.

But other research suggests that even many individuals with clinical hypothyroidism are taking too high a replacement dose. Altogether, combining the clinical and subclinical hypothyroidism populations, as many as 90% of these individuals may be taking more thyroid hormone than they need or is good for them.

Clinical issues

When I practiced psychiatry in San Francisco, there was a physician who promoted himself as a thyroid expert. People flocked to him for treatment of symptoms such as low energy, brain fog, and feeling fatigued or weak. He would always order thyroid blood tests, but regardless of the findings, including when the numbers were solidly in the normal range, he would tell his patients that they were actually hypothyroid and would benefit from low dose combinations of T4 and T3.

Many of his patients experienced feeling better. How much of that was due to the hormonal effects of the thyroid hormones, and how much to placebo effects, is hard to determine.

Decades ago, I worked with a patient who was genuinely hypothyroid, with a TSH level 30 times higher than the upper limit of normal. When she tried to take synthroid (levothyroxine, T4), to compensate for the deficiency, she had bad reactions. Even at an extremely low dose, within an hour or two of taking synthroid she would turn bright red, feel extremely hot, develop a hand tremor, become anxious, and feel a compelling need to pace or industriously clean her house.

Her endocrinologist prescribed a low dose beta blocker to try to block these apparent side effects. But even three or four pills of the beta blocker failed to make the synthroid tolerable.

The endocrinologist was puzzled regarding why her body was so strongly resisting a substance that she had formerly made and appeared to desperately need. The patient was also curious about her situation and was willing to engage in an experiment. She was aware that she would become progressively more ill if she didn’t get sufficient synthroid, but could only manage the lowest dose — less than one tenth of what she needed — twice a week.

The beta blocker and synthroid pills were the same size and color. I wrote numbers on several little paper cups, and my office partner placed either four pills of the beta blocker or three pills of the beta blocker and one of the low dose synthroid in each cup, and recorded the contents of each cup.

Initially, neither the patient nor I would know whether she took synthroid on a given day, but would be able to check the list retroactively. On the very first day of the experiment, she had a powerful, multi-symptomed reaction within hours of taking her pills. Her response was so overwhelming that I peeked at the list — and discovered that she hadn’t taken any synthroid that day!

Over the next two weeks she had several more violent reactions, along with days where she wasn’t bothered by the pills she consumed. There was no correlation whatsoever between what she consumed and her response. Some days she took synthroid and had no reaction. Some days she took no synthroid and had a robust response.

At the end of the experiment, I let her know that she had an amazingly strong placebo response. (Technically, this was a nocebo response — a strongly negative reaction to what she expected to take.) Her brain had created overwhelming reactions throughout her body; it wasn’t the synthroid that made her sick. She took a long while to accept this, but eventually learned to see that the ability of her mind to produce dramatic responses in her body could be an asset, not just a curse.

Decades later, that example still stands out as the most vivid example I’ve seen of the power of the placebo. Whenever other individuals have a strong immediate response to a medication, positive or negative, it leaves me uncertain as to whether they are having a direct physiological reaction, or a placebo/nocebo response. I do know that the individual’s certainty as to the cause of their response is not a useful indicator of what is actually transpiring.

I’ll stick my neck out here, by asserting that many individuals feeling better on low dose thyroid hormone therapy are experiencing placebo effects.

Natural or synthetic

For decades, the only source of replacement thyroid hormone was to use animal thyroids from slaughtered livestock, particularly sheep, cows and pigs. Fresh glands were initially used, but then production facilities reduced spoilage problems by desiccating and powdering the product. The T3 and T4 molecules produced by these farm animals are identical to those in the human body.

Dried animal sources of thyroid hormone were extensively used before the FDA began its modern drug approval process. Once thyroid molecules could be built in a laboratory, they gradually became the standard for thyroid replacement therapy. The synthetic product reduced the risk of contamination, not only from viruses, bacteria and fungi, but also from stray proteins that might provoke allergic responses.

The man-made thyroid hormones also provided much greater consistency regarding dosage. Many tests of desiccated animal thyroid products have found substantially lower or higher concentrations than indicated on the label. Furthermore, the ratio of T3 to T4 in pigs tends to be much higher than the ratio in humans. With more of the active form of the hormone immediately available, humans are more likely to feel a quick effect.

Some individuals experience better reactions to animal-derived thyroid hormone than to synthetic. How often this is due to expectation and placebo effects is hard to ascertain.

Overall, synthetic thyroid hormones are cleaner and more consistent than desiccated animal products, making them superior from a public health perspective that makes them clearly superior. For those preferring a product more directly tied to its animal origins, the FDA should have standards ensuring consistency and safety.

Rather than focusing on whether natural or synthetic versions of replacement thyroid hormone are preferred, more people should be considering whether they need to be on thyroid hormone at all.

If I’m not promoting nuance, I’m probably creating new angst.

A quarter of American adults worry that they have ADHD, and a majority want to reduce their screen time or social media use. Schools are limiting access to smart phones and electronic devices. Digital detoxes are a popular topic on — of course — the internet. But how much do they really help?

A plethora of anecdotal evidence indicates that after taking a digital detox many individuals feel more positive, think more clearly, and display less anxiety.

People can connect to the internet via desktop or portable devices, for differing lengths of time, at multiple times of day, and explore a multitude of online content. It’s not clear which of those variables may be causing the most damage to our cognitive functioning and ability to regulate ourselves.

Beyond just individual stories documenting the benefits of unplugging from the internet, researchers are beginning to demonstrate recovery of brain capabilities and improvement in well-being from digital detoxes. Several studies indicate that complete abstinence isn’t necessary for some of these benefits.

Our messy world

Online immersion is only one part of our modern culture harming our brains. Fractured sleep, inadequate exercise and diets, increased ambient temperature, and the proliferation of plastic pollution permeating our brains are among the other factors contributing to diminished prefrontal cortical performance. This part of the brain is associated with abilities such as sustaining attention, inhibiting impulses, planning, and regulating emotions.

Excessive internet use interacts with many of these other detrimental factors. Time online competes with taking good care of ourselves with proper sleep, exercise, and diets. The computer and AI industries add to the cumulative burden of toxic plastics and metals released into our environment and consume vast amounts of energy contributing to global warming.

Changing some of these factors is outside the capability of individual action, but how much time we spend online, and how we spend it, is, at least theoretically, something we can control to improve the functioning of our brains.

Much of the public discussion of the negative impact of computer culture on human thinking focuses on our collective deterioration of sustained attention. Terms such as “attention economy” capture this context. But other common descriptors, like “digital dementia” and “popcorn brain” highlight that this internet is not just impairing attention or causing troubles with attention.

A number of other executive functions of the brain — how it manages and organizes information processing — from memory, to organizing and executing tasks, managing time, regulating emotions, inhibiting fidgeting, and curbing impulsive behaviors are all impaired by excessive, problematic time spent with our computational/communicative devices.

In addition, online time can degrade our sense of wellbeing and contribute to symptoms of depression, anxiety, and loneliness.

It’s not all bad

Computerization hasn’t created only misery. In our digital world, we have rapid access to vast stores of information — far more facts are more easily accessible than visiting even the largest libraries of past generations.

The internet also allows individuals to connect despite vast distances. That means family and friends can remain in communication regardless of travel or moving to new locations. Also, communities can be built among previous strangers based on shared interests, values, backgrounds and identities.

Digital technology has allowed researchers to sift through vast volumes of data and find patterns and correlations undetectable to unassisted human minds. It has created opportunities to design and test scientific hypotheses that can lead to deeper understanding and more effective treatments.

Mental health is benefitting from these advances. One recent example of this is the detection of biomarkers based on patterns of brain interconnectivity that identify specific subtypes of ADHD. Another study used an EEG neurofeedback approach for meth addiction based not on the activity within specific brain regions, but on a composite map of neurons firing across the entire brain. Neither of these projects would have been viable without the huge data crunching capabilities currently available.

Digital downsides

On the downside, our brains didn’t evolve to handle so much information so rapidly. This new onslaught of stimulation is rewiring and damaging our brains. Rewiring occurs because the brain adapts to the inputs it receives, and strengthens the circuits it uses while allowing neglected connections to atrophy.

Damage occurs because some parts of the brain just can’t cope with the workload.

The brain is often compared to a muscle. While there is some value in this analogy, in other aspects it falls apart. Unlike most of our skeletal muscles, which fatigue if you exercise them too much, most parts of the brain don’t tire out. You can process visual information all day long, and at the end of the day shapes aren’t losing their sharp edges, and colors don’t drain from images. The neural signals that keep your heart beating and lungs breathing don’t need to rest at night time.

But much of the prefrontal cortex does behave like a muscle, and fatigues with overuse. This is largely due to the heavy reliance on a specific type of glutamate receptors, called NMDA receptors, in the brain. Functioning of the circuits relying on these NMDA receptors decreases if they are activated for too long.

Many of our executive functions in the prefrontal cortex employ these NMDA receptors. If you try to remain vigilant and attentively focused for too long, concentration starts to wander. Similarly, the ability to resist impulses wanes with time.

Furthermore, not only do some of these executive functions demonstrate fatiguability, when their performance degrades it can also affect adjacent circuitry. This bleed-over effect is thought to reflect the abundance of glutamate sloshing around in this part of the brain. It means that when attention has been depleted, that can affect nearby networks, making it harder to regulate emotions, manage time, plan activities, or stop fidgeting.

Looking at those devices

A number of studies have found that excessive time spent plugged into devices is associated not only with diminished attention, but with poorer impulse control, lower mood, greater hyperactivity, and less ability to modulate emotions.

Many of these studies are observational, or just looking at what people do and detecting an association with an outcome. That can’t tell us whether the behavior actually caused a good or bad outcome.

For example, it’s possible that people who, to begin with, were more distressed, or had less ability to concentrate or were feeling more anxious or a greater degree of social disconnection, then gravitated to spending more time on online engagement than did their peers.

Very likely, at least some of the findings from the digital immersion research reflect feedback loops. People with certain traits are more likely to use the internet in problematic ways, which further diminishes some of their executive or social functioning and leads to even greater immersion in the digital world.

Another challenge of designing and conducting digital toxicity/detox studies is that we don’t know what aspects of our digital culture are most damaging.

The ways in which too much computer time is harmful could be mediated through:

• the volume of information

• the speed of delivery of information

• the extent to which information disrupts/intrudes on other activities

In addition, the content of information one exposes oneself to may matter. Looking up information or watching an entertaining video has different impacts than spending time on social media. Exposure to misinformation and disinformation is likely to have detrimental effects.

Studies that make different interventions regarding what type of digital information is restricted are likely to result in different results.

Digital detox research

An entire genre of books touts the benefits of digital detoxes, exemplified by the personal experiences shared by Johann Hari in Stolen Focus (2022) or Jenny Odel in How to Do Nothing: Resisting the Attention Economy (2019).

Beyond the anecdotal, more systematic studies include a 2025 Harvard-based study that generated a fair amount of media attention. The researchers blocked 373 young adults (average age 21, 73% female) from five social media apps (Facebook, Instagram, Snapchat, TikTok, and X) for one week.

Their daily use of social media declined from 1.9 to 0.5 hours, although screen time actually increased somewhat. Subjects displayed a small improvement in mental health measures of mood and anxiety, although loneliness did not change.

However, the researchers concluded that the correlations were fairly small, and felt that problematic use (feeling distressed when using social media) was a better predictor of who benefitted from a digital detox, than was the amount of time someone spent online at baseline.

Another 2025 study, led by behavioral economist Noah Castelo at the University of Edmonton, recruited 467 subjects (average age 32, 63% female) who were motivated to block mobile internet access for two weeks. This study specifically:

• allowed mobile texts and calls

• allowed subjects to have internet access via desktops

• monitored internet use rather than relying on subjects’ reports

After two weeks without mobile internet use, the subjects showed:

• marked decrease in screen time (almost 50% reduction)

• marked improvement in subjective well being

• marked decrease in depression (comparable to therapy)

• marked increase in objectively measured attention

In addition, the researchers explored possible mechanisms by which these improvements might have occurred. They found that for the improvement in mental health and of subjective well being, all of these mediators played a role:

• increased time spent in the offline world

• decreased time spent consuming media

• increased social connectedness

• improved feelings of self-control

• increased sleep

Interestingly, the effect of the first four social/behavioral mediators was considerably larger than the impact of improved sleep on good outcomes. Also of note was that none of these factors appeared to be modulating the improvement in objectively measured attention. These findings support the conclusion that our digital world is acting through multiple pathways to harm our brains, but that much of this can be corrected through a relatively brief abstinence.

Although these individuals were highly motivated, according to their own self-assessment, to reduce their mobile internet use, only 26% of them completed the study and blocked their use for at least 10 of the 14 days of the detox. However, substantial benefits accrued even in those who did not strictly adhere to the design of the study, and experienced a partial detox.

The findings from a 2023 German study are generally consistent with these other studies. The researchers studied 600 subjects, one third of whom kept using their smartphones, another third of whom were instructed to reduce their use by one hour a day, and the third group who were supposed to forgo use entirely for one week.

Both detox groups had a reduction in smartphone use, less problematic smartphone use, increases in well-being and physical activity, and decreases in depressive and anxiety symptoms.

However, most of the effects were stronger and more lasting in the group with an hour reduction rather than the complete abstinence group. It is very likely this is not because an hour reduction is “healthier” but rather because the subjects who did so learned ways to put limits on their digital use, whereas the all-or-nothing group probably experienced some Fear Of Missing Out during their time away from their phones, but also didn’t develop or practice techniques to control their use.

Conclusions

All research on digital detoxes is plagued by the subjects knowing that they are undergoing an intervention that is likely to make them feel better. It is hard to eliminate the placebo/expectancy effect, but studies might try to compare the benefits of a digital detox to other mental health treatments known to be helpful.

From the evidence so far, many people will feel better and think more clearly after a digital detox. Better yet, complete abstinence is not essential for producing benefits.

A simple starting approach might involve restricting use from certain hours of the day, days of the week, or during specific activities. Maybe instead of meals and meetings being me-time when you’re on your phone, you could make them a time to connect with others.

If you have trouble restricting yourself, there are widely available apps that can shut off your phone access at specific times, or restrict your time on certain apps or platforms.

Research so far is encouraging that many of the damaging effects of immersion in our digital world are reversible. But that doesn’t rule out the possibility that some patterns of behavior, carried out long enough, might cause permanent problems. People are likely to vary in their threshold for enduring injuries.

I often tell my patients that if a habit or practice doesn’t feel sustainable, it probably won’t be. If you benefit from a digital detox, it’s a sign that you’re been poisoning yourself. Ultimately, you want to learn how to rein in your daily digital use so that you don’t need a designated detox to feel better.

Learn to view your cellphone as a reminder to be mindful of why you’re using it at this moment.

Dr. John Kruse’s next book, ADHD World: Why We’re Losing Focus and What to Do About It touches on some of the themes of this article and will be published September 1, 2026 by New Harbinger Press.

If I’m not promoting nuance, I’m probably creating new angst.

Life is hard. Lots of people would like to be smarter in order to deal with its challenges and increase their likelihood of success. Piracetam, developed in 1964, was billed as the first smart drug, or nootropic — something that would improve cognition but didn’t just jack up activity throughout the brain.

Piracetam is widely used in parts of Europe, Asia, and Australia for dyslexia, traumatic brain injury, dementia, vertigo, ADHD and other brain-based conditions. Yet the FDA has never approved it as a medication for treating any condition, nor does it sanction it as a supplement.

While it is legal to possess and consume piracetam in the US, it is against the law for doctors to prescribe it or for companies to manufacture it, import it, or sell it. So Americans using piracetam are, in a sense, pirates — appropriating and benefiting from a substance that they’re not supposed to have access to.

The FDA has deemed the evidence supporting the use of piracetam for any condition to be weak and inconclusive. The science showing that piracetam boosts brain functioning in healthy individuals is even more sparse. But lack of evidence isn’t proof that it can’t work.

So what do we really know about piracetam?

Ahoy, matey, here’s piracetam for ye

Piracetam doesn’t actually have anything to do with pirates. Rather, its discoverer, Romanian neuroscientist Corneliu Giurgea, coined the name to describe the molecule’s structure, which combines a four-carbon, one-nitrogen pyrrolidine ring with a short acetic acid-amide chain.

Piracetam’s shape is very similar to the second most common neurotransmitter in the brain: gamma-aminobutyric acid (known as GABA to friends). However, piracetam does not bind to any GABA receptors.

In fact, unlike many of the drugs that have prominent effects on the brain, piracetam doesn’t bind to, activate, or block any of the conventional neurotransmitter receptors. Nor does it open ion channels to change the propensity of nerve cells to fire.

Pharmacologists have yet to fully decipher piracetam’s mechanism of action, but research indicates that it primarily affects cell membrane fluidity and flexibility — and it does so throughout the body.

Within the brain, changing the properties of neural membranes alters how neurotransmitter receptors function. Piracetam modulates neural connections that rely on acetylcholine, glutamate, serotonin and dopamine. This leads to up or down-regulation of the abundance of certain receptors, with glutamate (both AMPA and NMDA varieties), dopamine-2, and serotonin-2 receptors in particular being affected.

Piracetam’s effects on membranes also appear to mediate how it improves the functioning of mitochondria, reduces damage from oxidative stress, protects neurons, and promotes the strengthening of synaptic connections between neurons.

Piracetam’s membrane effects extend to the vascular system. It alters the permeability of small blood vessels and decreases the clumping of red blood cells. This is why it is occasionally used to treat blood clotting crises in sickle cell anemia, as well as why it can cause excessive bruising and other problems when combined with conventional blood “thinning” agents.

Chemists have developed additional drugs by modifying piracetam. Levetiracetam (Keppra) is structurally very similar to piracetam, yet has strong anti-seizure action and minimal cognitive effects.

Several racetam derivatives of piracetam, including pramiracetam, aniracetam, oxiracetam, and others, have been designed to be more fat soluble so that they sail more easily into the brain, with greater potency in boosting cognitive functions.

Piracetam across the seven seas

Giurgea didn’t just discover piracetam; in 1972, he also coined the term nootropic, for drugs that improve cognitive functioning. The word comes from Greek roots, noo- meaning mind, and -tropos meaning to grow or bend.

Giurgea’s use of the term nootropic specifically excluded drugs that enhanced brain function by serving as a stimulant. However, many people today refer to medications such as methylphenidate (Ritalin) and modafinil (Provigil), which have some stimulating properties, as nootropics. The term “smart drug” is a less formal and less precisely defined version of “nootropic”.

In many countries, methylphenidate, modafinil, and piracetam are used so frequently that they can be detected in wastewater. Furthermore, modern wastewater treatment plants don’t effectively clear these drugs before returning the water to customer water supplies. I guess it’s nice to share, (even if it’s not something pirates are known for), but it certainly doesn’t seem to be making the world a smarter place.

Piracetam is widely used throughout continental Europe, Australia and Japan as a prescription medication. It can be legally obtained over the counter in Brazil, Russia, Ukraine, and Czechoslovakia. But in the US and Canada, it has never been approved as either a medication or a supplement.

Although companies are expressly forbidden to manufacture, import or sell piracetam in the US, nevertheless, many do so, marketing their products as brain enhancers. Some companies mention piracetam on their labels while others include it without disclosing the fact. So far, the FDA, while aware of this practice, has not brought major actions against these companies.

A sinking ship?

Despite decades of use and increasing interest in biohacking and brain enhancement (aye matey, how else are we going to keep up with AI?), general interest in piracetam has actually waned in the last decade, while searches for other smart drugs like modafinil have surged.

Similarly, research on piracetam has shown a marked drop-off, with only about 50 articles annually being published in the last ten years, whereas more than 200 articles a year were being churned out in the previous decade.

Curiosity about some of the other, more effective, racetams may account for a small part of the drop off in interest in piracetam. Whether the bulk of the decline reflects mere complacency about piracetam (it’s been around so long and used so much) or dissatisfaction (it doesn’t help that much) remains unclear.

What ye landlubbers need to know

In countries where piracetam is approved, the most common indications include:

• dementia

• traumatic brain injury

• vertigo

• dyslexia

• autism

• ADHD

• cortical myoclonus (involuntary muscle spasms triggered by the brain)

• sickle cell anemia crises

For most of these conditions, any supporting studies indicating that piracetam might be effective were conducted thirty or forty years ago. Furthermore, most of the studies were small, and conflicting studies finding no effect from piracetam have also been published.

Regarding dementia, although a 2002 meta-analysis claimed “compelling evidence for the global efficacy of piracetam in a diverse group of older subjects with cognitive impairment”, a larger, more comprehensive 2024 analysis declared that the existing research is so inconsistent and of such poor quality that “It couldn’t be ensured that piracetam positively affects memory.”

For ADHD, a few studies in mice indicated that piracetam could alter neurotransmitter receptors relevant to the condition, as well as improve symptoms resembling ADHD behaviors. But the drug had different effects on different mouse strains, making it unclear how relevant that basic research is to the brains of humans with ADHD.

Only a handful of randomized controlled studies exist for piracetam as a treatment for ADHD. When used alone, piracetam provided benefits similar to Strattera (atomoxetine), albeit working more slowly and less potently. Another study indicated that for subjects already taking a stable dose of Ritalin (methylphenidate), the addition of piracetam, compared to placebo, enhanced further reduction in ADHD symptoms.

For all of the other conditions for which piracetam has been approved, the story is similar. There’s more animal research than human research, and the results in humans have been small studies, with inconsistent results.

As far as the possible benefits of piracetam on healthy brains, there’s even less research to base any conclusions on.

It’s important to point out that the current lack of strong evidence doesn’t prove that piracetam is ineffective. It’s just that after a half century, we’ve done a pretty poor job of showing that it really works. This is also true for other racetam derivatives, some of which, like aniracetam, have been around now for forty years; they also lack compelling research showing that they help human brains.

Shiver me timbers! What’s a body to do?

For substances that haven’t been studied extensively, there are two big risks to taking them to either treat a condition or improve normal functioning.

The first is the risk of side effects or damage. Regarding piracetam, it’s been used widely enough that it’s clear that it’s quite safe and that side effects tend to be infrequent and mild. Toxicologists report that regarding potential lethal effects from overdoses, piracetam is safer than table salt.

It’s extremely unlikely that any individual will harm themselves by trying piracetam.

The second risk is what economists call an opportunity cost — that choosing a potentially ineffective option may prevent individuals, because of the restraints of time or cost, from pursuing more effective treatments. Getting enough sleep, restricting your social media time, eating a healthy diet, and getting sufficient exercise are more effective and better-tested ways to take care of your brain than popping a piracetam pill.

Experts are under attack in our modern era. It’s popular to reject expert opinion, even at the highest levels of governments — where we’ve seen some spectacular failures as a result.

Expert opinion isn’t valuable because it’s always right. It’s valuable because it is more often right than uninformed assessments or random guessing. Furthermore, expert opinion often offers a clear explanation should failure happen. And finally, when it’s scientifically based, expertise learns from experience, and improves with time.

Anecdotal information isn’t worthless. Many people feel that piracetam has helped their brains work better. But given the power of placebo effects and expectations, anecdotes can’t really tell us whether piracetam actually helps. So far, only science can tell us that.

Whether the FDA is too cautious or too lenient isn’t usually fundamentally a question of science. It’s more a value judgment regarding how strong evidence needs to be before approving a given medication, and how we weigh the relative risk of side effects against potential benefits. While not perfect, the FDA has a pretty good overall track record.

So if you want to walk the plank, you could try piracetam. But a smarter move would be to engage in the healthy behaviors that we already know improve and sustain brain performance.

If I’m not promoting nuance, I’m probably creating new angst.

Why does ADHD exist?

Genes play a major role in determining who develops Attention Deficit Hyperactivity Disorder (ADHD). ADHD is the most common neurodevelopmental condition in childhood, with a substantial proportion of those children continuing to be affected throughout their adult lives. ADHD isn’t just a minor annoyance. It’s associated with significant reductions in academic, financial and relationship success, and even shortens lifespans.

If genes contributing to ADHD have a detrimental impact on health, why did they become established in ancient humans? The most common explanations are mismatch theories — that ADHD genes were adaptive in some way for our ancestors, yet are detrimental in our modern lives.

But a more direct explanation also exists. A number of studies indicate that those with ADHD have sex at a younger age, with more partners, and with less thought regarding the potential outcomes from sexual activity. Particularly in times before the widespread availability of birth control, more sexual activity would result in more offspring in future generations with those ADHD genes.

Maybe ADHD’s existence isn’t because certain genes made us better hunter-gatherers or explorers, but simply because it led to more sex.

Stud-ying sex

Before exploring the connections between ADHD and sexual behavior, it’s worth diverting into why and how researchers study sex. Sex researchers aren’t just indulging in their own prurient interests. As a fundamental behavior driving human existence, sex is important. From a public health perspective, risky sexual behavior has major implications. Sexually transmitted diseases (STD) aren’t just icky; some, like HIV and syphilis, damage organs throughout the body and kill people. The STDs that don’t kill people can still impact fertility.

The other major outcome of risky sexual behavior is children. Individuals who reproduce before they’re ready to be parents place a big burden on society.

Reports of sexual behavior can be notoriously unreliable. For example, in clinical research studies, reports of the rate of sexual side effects from the serotonin specific reuptake inhibitor (SSRI) fluoxetine (Prozac) range from the incredibly low 0% to the amazingly high 80%. What contributes to so much variance when the modern consensus is that at therapeutic doses Prozac causes either libido suppression or orgasmic delay in approximately a third of users?

Responses about sexual behavior depend strongly on what individuals are asked.

In early studies of Prozac, investigators were not aware of the possibility of sexual side effects, didn’t specifically inquire about them, and subjects didn’t volunteer information about their sexual behavior, which was often considered a private matter. This resulted in studies not finding any detectable sexual side effects, or rates in the single digits. Once it became known that SSRIs commonly caused sexual side effects, investigators knew to ask about them, and patients became more comfortable mentioning them.

The few studies finding very high rates of sexual side effects from SSRIs are not tallying responses to specific inquiries about libido, erectile dysfunction, or orgasmic difficulties. Rather, the high rates are in response to a very broad question regarding whether the subject’s sex life was in any fashion less than optimal. It turns out a lot of people are dissatisfied with their sex lives.

Not only does it matter what you ask, but it also matters who you ask. After decades of reading articles on SSRI treatments, my observation (and not one I have rigorously documented) is that studies done on American populations tend to have significantly higher rates of many side effects (nausea, headaches, sleep disturbance) than in European populations.

This difference is particularly noticeable regarding sexual side effects. I doubt that the SSRIs work differently on the other side of the Atlantic, or that the Europeans are all having more and better sex. Instead, different cultural standards and expectations shape how individuals think about and respond to questions about personal behavior, and affect the likelihood of acknowledging disappointment in one’s sexual life.

Who’s asking the questions can also be a factor. Subjects tend to be more candid when asked personal questions by individuals perceived to be of a similar age, gender and ethnicity. People are also more likely to endorse potentially embarrassing behaviors when the questions come from a computer rather than a human.

The challenges with assessing human sexual behavior infiltrate the studies on sexual behavior, yet the findings about sexual behavior among those with ADHD have been largely consistent. Finally, it’s important to emphasize that even when group averages show significant differences, this does not mean that every individual with ADHD aligns with their group or deviates from social averages with regard to sexual behavior.

Genes and ADHD

Twin and adoption studies revealed decades ago that genes strongly influence the likelihood of developing ADHD. For years, researchers hoped to identify a “candidate gene” — say for a dopamine receptor or transporter, that would “explain” most of ADHD. But it’s clear now that ADHD arises from polygenic factors — hundreds or even thousands of genes each playing a tiny role.

Adding to the genetic complexity, many of those genes, particularly those affecting proteins that are used throughout the body or that shape how organs, including the brain, develop, have multiple effects on many different features of the individual who inherits them. The fancy word for this is pleiotropy.

Pleiotropy is part of why anyone should be skeptical about evolutionary explanations for why certain genes persist. Although we may focus on the role of genes that increase the likelihood of developing ADHD, each of these genes is almost certainly having other, potentially more important, impacts on human health. This means that ADHD, or almost any trait or condition, might arise simply as a side effect of a gene’s primary and positive role in the body.

However, genes that cause impairment from an early age and predispose to early death, as is the case with ADHD, tend to be selected against. This suggests that genes for ADHD provided some powerful, countervailing benefit to our ancestors, or else they would have been eliminated long ago by natural selection.

The most prominent mismatch theory proposes that those with ADHD traits performed well in hunter-gather societies, and that the advent of highly structured, predictable, linear constraints imposed by agriculture has made ADHD disadvantageous. However, genetic evidence suggests that the frequency of genes associated with ADHD has been declining in human populations for at least 45,000 years, substantially predating the rise of agriculture. Another variation of the mismatch theory posits that the ADHD trait of novelty-seeking predisposed people to be explorers and immigrants, ensuring the widespread proliferation of these genes.

The evidence that ADHD genes have been declining for millennia should not be confused with a recent study showing that over just the last few decades, the genetic contribution to ADHD appears to have decreased by a measurable degree. The most common explanation for the decreasing genetic influence is that as the definition of ADHD has become somewhat more inclusive, individuals who previously would not have been diagnosed with ADHD now receive that label. As a result, we may be including people with milder forms of the condition under the ADHD label.

However, another explanation is that our world has changed through the advent of pervasive online technology, and decreases in sleep, activity, healthy diets and exposure to nature, so that people who are slightly less genetically predisposed to ADHD are now developing the full-blown clinical condition because their environments are so strongly pushing their behavior and thought processes in an ADHD direction.

Regardless of the reasons for slight decreases in the abundance of genes predisposing for ADHD, it appears that in the distant past, the relative benefit from possessing ADHD genes was greater than it is now.

Sex and ADHD

Despite the challenges in studying sexual behaviors, research indicates that teenagers and young adults with ADHD, compared to their peers without ADHD, are more likely to:

• initiate sexual behavior at earlier ages

• have a larger number of partners

• have more unprotected sex

• contract more STDs

• have higher sexual drive (at least in males)

• engage more often in masturbation

• experience less sexual satisfaction.

Collectively, the first four activities are categorized as sexually risky behavior. In the absence of birth control, risky sexual behavior is also more likely to lead to producing children and passing on one’s genes.

In general, both males and females with ADHD are more likely to engage in sexually risky behavior. This risky sexual behavior aligns with other ADHD behavior; individuals with ADHD need or desire greater levels of stimulation, seek more novelty, and become bored more readily.

Greater impulsivity, a central feature of ADHD, can lead to risky sexual behavior. In particular, those with ADHD overestimate the immediate benefits of having sex.

They also display greater delay discounting, whereby future negative outcomes shrink in importance the further away in time that any bad result might occur. If a sexually transmitted disease isn’t going to show up for days or weeks, or a newborn won’t arrive until nine months from now, those with ADHD have greater difficulty holding on to the impact of such potential repercussions and inhibiting their current actions to account for such outcomes.

Research indicates that not only impulsive, but also inattentive ADHD traits can increase the likelihood of sexually risky behavior. Troubles with planning (“I didn’t have time to buy a condom.”), distractibility (“They were so sexy I forgot that I had brought protection with me.”) and forgetfulness (“I didn’t remember to take the pill this morning.”) constitute inattentive symptoms that could lead to unplanned or unprotected sex.

Results from Africa, Russia, Asia, and Europe appear similar to American studies, suggesting that the impact of ADHD on sexual behavior is not simply a cultural artifact. The impact of ADHD on sexual behavior contributes to the pattern of intimacy issues in those with ADHD, which indicates that individuals with ADHD tend to have shorter, and more numerous, relationships across their lifetime.

More doesn’t mean better

Despite the association between ADHD and a stronger libido, initiating sex at younger ages, and having a greater number of sexual partners, more isn’t always better. In addition to contracting more STDs, and greater dissatisfaction with their sexual lives, those with ADHD tend to have a greater frequency of clinical sexual dysfunction.

Among men with ADHD, rates of premature ejaculation are particularly high, reaching 40% in several studies, more than ten times greater than the rate among males without ADHD. Among women with ADHD, some research indicates that a majority face orgasmic difficulties. Although premature ejaculation and orgasmic difficulties may cause significant distress, neither directly impacts fertility, and thus they face less selective evolutionary pressure for their elimination.

Early hormonal exposure may explain part of the association between ADHD and sexual dysfunction. Higher maternal testosterone levels during pregnancy are associated with both higher rates of ADHD and sexual dysfunction among the offspring.

What we consider to be “risky” sexual behavior in our modern environment may have simply been frisky sexual behavior for thousands of generations of human existence. The simplest, most direct explanation for the existence of ADHD is that evolution favored genes that got you out of your jeans.

If I’m not promoting nuance, I’m probably creating new angst.

Public service announcements have bombarded us for years with the message that Vitamin D from milk, sunshine, or other sources is important for building strong bones. So the results of a recent meta-analysis confirming a strong association between Vitamin D deficiencies in mothers and the development of ADHD and autism in their children may seem surprising.

Vitamin D is important for much more than a sturdy skeleton. Vitamin D receptors exist throughout the body, including the brain.

Numerous internet sites promote Vitamin D supplements, tout the purported benefits of raw milk, or encourage men to tan their testicles to elevate Vitamin D and testosterone levels. Understanding what Vitamin D is and how it works can help you sort through what is nonsense and what you can do to maintain a healthy body and brain.

To begin with, Vitamin D isn’t even really a vitamin….

Vitamins are vital

Vitamins are organic (in the sense of carbon-based, rather than farmed without synthetic chemicals) molecules that humans need in trace amounts from their diet in order to survive. “Vit-” means life, and “amin” came from the mistaken belief that all vitamins were amines, a specific type of ammonia-based organic compound.

The term vitamin distinguishes these compounds from essential minerals, like copper, magnesium, and sulfur, which we also require in trace amounts. Vitamin also helps differentiate chemicals that we need in tiny amounts from macronutrients, (fats, carbohydrates, proteins) that we need in much larger amounts.

Most vitamins were discovered because their absence from the diet caused a specific disease. Childhood deficiencies in Vitamin D produced rickets, a condition of stunted growth and weakened bones. Vitamin D was the fourth vitamin discovered, after A, B, and C, and before it was understood that there were multiple B vitamins.

For most of human history, people obtained all of the Vitamin D they required after their skin was exposed to sunshine. They didn’t need an external, dietary source, which is why, technically, Vitamin D isn’t a vitamin.

The discovery of vitamins, and ensuring adequate intake of them through food or supplements, banished many of the diseases their deficiencies had produced. It’s why you don’t hear crickets about rickets anymore. The discovery of Vitamin D is also one of the factors that led to making factory farming possible; supplementing animal feed with Vitamin D enabled livestock to grow under conditions when they were shut away from sunlight.

No dosing off

Two basic forms of Vitamin D exist: D2 (ergocalciferol) and D3 (cholecalciferol). D2 comes from plants and fungi, including edible mushrooms. D3 is produced by the skin after exposure to ultraviolet B (UVB) light, and is also naturally available from a few food sources. Fatty fish are rich in Vitamin D3, which is also present in cow liver and egg yolks.

In modern societies, several foods, including milk (cow, soy, almond, oat and rice), orange juice and cereals, provide Vitamin D3 because they have been fortified. A glass of fortified milk contains about 100–150 International Units (IU) of Vitamin D. A glass of natural raw cow’s milk contains only about 10 IU. The levels of Vitamin D can be boosted to possibly 20 IU if the cow receives plenty of sunshine and is supplied with feed enriched with Vitamin D.

As a reference, the current US Recommended Daily Allowance (RDA) is 600 mg IU for most Americans and 800 IU for those above age 70. In addition to exposing individuals to potentially dangerous pathogens, under the best conditions someone would have to drink about two gallons of raw milk every day if they were trying to meet Vitamin D daily requirements through their diet.

However, just a few minutes of full body exposure to sunshine can induce your skin to produce 10,000–25,000 IU of Vitamin D. But that depends upon the:

• amount of skin exposed

• time of day

• time of year

• latitude

• skin pigmentation

• absence of sunscreen or sunblock

A few years ago, scientists calculated that a white British individual in t-shirt and shorts could secure their daily requirement of Vitamin D with close to nine minutes of midday sun exposure during the summer, but would need more minutes during other times of the year. Even the southernmost parts of Britain are further north than the Canadian-US border.

The season, time of day and latitude matter because ultraviolet B rays are most intense in the middle of the day, closer to the equator, and during summer months.

Melanin and sunscreens block UVB. Normal window glass also blocks almost all UVB, while allowing longer wavelength UVA through. Darker skinned individuals need considerably more time in the sun to generate enough Vitamin D, and on average show consistently lower circulating levels of Vitamin D and higher percentages of individuals in Vitamin D deficient states.

Too much?

The skin cells that manufacture Vitamin D respond to Vitamin D levels, creating a feedback loop which shuts down generation of Vitamin D when blood levels are adequate. This prevents overdosing on Vitamin D from skin exposure.

Being one of the fat soluble vitamins (along with A, E and K), Vitamin D tends to last a long time in the body, and therefore creates a potential risk of overdose or toxicity if levels were to build up too high in the body. The water soluble B and C vitamins tend to be quickly eliminated in the urine.

Most of the symptoms of too much Vitamin D are related to increased body calcium levels. This can produce nausea, vomiting, excessive urination, excessive thirst, weakness and confusion. If it lasts long enough, it can lead to bone pain, kidney stones, kidney damage, and heart rhythm irregularities.

For most individuals, supplementation with up to 4000 IU daily is generally considered safe. But anyone regularly taking Vitamin D supplements should communicate this fact to their doctor, so they can be appropriately monitored.

More chemistry

Both Vitamin D2 and D3 are inert molecules that need to be converted by the liver into 25-hydroxyvitamin D. Confusingly, 25-hydroxyvitamin D has two additional, interchangeable names: calcifediol or calcidiol.

Calcifediol is the major circulating form of Vitamin D in the body. Standard blood tests for Vitamin D are usually measuring calcifediol. Most of the calcifediol is bound to proteins in the blood, and is not “free”.

Calcifediol lasts for weeks to months in the body. Some people with Vitamin D deficiencies take calcifediol supplements, either because it is more readily absorbed by the intestine than D2 or D3, or because it doesn’t require a fully functioning liver.

However, calcifediol isn’t the end of the story. It needs to travel to the kidneys, for one more chemical modification, to become calcitriol, or 1,25-dihydroxyvitamin D, which is the biological active form of the vitamin. Calcitriol has a very short half life, on the order of minutes, and levels fluctuate quickly in response to calcium levels.

The need of a functioning liver and kidney to convert Vitamin D3 to an active form of the vitamin exposes the silliness of the scrotal tanning craze. Healthy Vitamin D levels can promote testosterone production in men. But any skin exposed to sunlight will produce Vitamin D3. There’s no special direct path for Vitamin D produced by scrotal skin to effect the nearby testicles — the Vitamin D3 has to travel to the liver, and next to the kidneys, and then back to the gonads before it could help them boost testosterone.

Going nuclear

Calcitriol works by penetrating cell membranes and then entering the nucleus of cells, where it binds to a special vitamin D receptor. After binding to the receptor, calcitriol activates certain genes.

Vitamin D’s biggest job in the body is to regulate calcium levels. Calcium is the most abundant mineral in the body, accounting for about 2% of our bodies by mass. Most of that is stored as calcium phosphate inside of our bones.

The primary organs regulating the balance of calcium and phosphorous in the body, all of which contain an abundance of Vitamin D receptors, include the:

• small intestine — regulating calcium and phosphorous absorption

• bone — particularly the cells (osteoblasts) making new bone

• kidney — regulating reabsorption of calcium

• parathyroid gland which makes a hormone up regulating calcium levels

Calcium’s role in the body isn’t limited to building bones. Every contraction of muscles, including your heart, requires an influx of calcium ions. Every firing of a neuron in your brain or body requires calcium ions to flow in before a neurotransmitter is released.

Calculating beyond calcium

Vitamin D’s role in the body goes beyond simple calcium regulation. A number of tissues contain Vitamin D receptors:

• immune system T-cells, B-cells and macrophages

• skin cells and hair follicles

• muscle cells

• brain cells

Vitamin D plays an important role in regulating the immune system. It’s vital for normal hair and skin growth. In the muscles Vitamin D not only enables contracts through the flow of calcium ions, but it also plays a role in muscle strength.

The hypothalamus of the brain contains abundant Vitamin D receptors, so Vitamin D influences the release of hormones, modulates circadian rhythms, and helps adjust basic drives such as thirst, hunger, sex and sleeping.

Additional brain areas rich in Vitamin D receptors include:

• substantia nigra, an area of dopamine production important in control movement

• hippocampus involved in memory formation and storage

• amygdala which regulations emotional processing

• thalamus which is a relay station for motor and sensory pathways

• prefrontal cortex involved in complex functions like thinking, and language.

Vitamin D on de brain

Vitamin D has multiple effects on the brain:

• shaping brain cell differentiation during childhood

• promoting nerve growth factors

• regulating immune system cytokines within the brain

• promoting neurotransmitter synthesis, particular dopamine and serotonin

• preventing damage from excess calcium flowing into neurons

• antioxidant activity preventing free radical damage

• altering gene expression and protein formation

Given the multitude of ways in which Vitamin D affects the brain, it isn’t surprising that low Vitamin D levels have been consistently associated with a number of mental health conditions, including schizophrenia, depression, autism, ADHD, and dementia. This causes many people to jump to the conclusion that Vitamin D supplementation might treat any of these conditions.

However, the association between low Vitamin D levels and these conditions doesn’t mean that a deficit in Vitamin D causes these conditions. In fact, reverse causality is almost certainly a significant source of the association. In our current world, having any of these mental health conditions leads to spending more time indoors, with less exposure to sunshine. These conditions also contribute to poorer nutrition. So having any of these mental health conditions can be the cause of lower Vitamin D levels.

A number of small studies on individuals who have both depression and low Vitamin D indicate that, at least in the short term, Vitamin D supplements can help improve mood. But one of the largest randomly controlled studies ever done in psychiatry, conducted on 18,000 individuals over the course of more than five years, found no benefit from widespread Vitamin D supplementation in decreasing the emergence of depression. So Vitamin D doesn’t appear to have widespread antidepressant properties, although supplementation can help with mood in those with low Vitamin D.

Some of the older studies on mental health and Vitamin D failed to control for the effects of Vitamin D on calcium levels. When calcium is too high or too low, it can also impair neural and brain functioning, making it hard to differentiate whether any problems that arise come from aberrant calcium or Vitamin D levels.

Even in situations where Vitamin D deficiencies may contribute to the development of a condition, it doesn’t mean that Vitamin D supplementation once the condition is detected will restore full functioning.

Several meta-analyses find that in humans, low Vitamin D in a mother during pregnancy is associated with higher rates of ADHD, and autism spectrum conditions, years later among her children. Vitamin D deficient rats also tend to have offspring with high levels of hyperactivity and impulsivity, hallmarks of ADHD. But Vitamin D supplements given in the third trimester to over 700 pregnant women with low Vitamin D levels failed to diminish the likelihood, a decade later, that their children would develop ADHD or ASD.

Because Vitamin D can influence brain development, deficiencies early in life might lead to subtle structural changes in neural connections that aren’t simply resolved by supplementation with Vitamin D later in life.

However, a handful of small, random controlled studies using Vitamin D supplements in children who have both ADHD and low levels of Vitamin D, demonstrated some reductions in ADHD symptoms.

Research has also found that Vitamin D supplementation in adults lowers the likelihood of developing dementia, as well as slowing progression of dementia when it is present.

Too much screen time

Studies indicate that two thirds of Americans have either deficient (usually defined as below either 20 or 25 ng/ml) or insufficient levels (25–75 ng/ml) of Vitamin D. Most of this is attributed to spending most of our lives indoors, often facing some form of computer screen, and when we do go outside, we’ve been warned by dermatologists to put on sunscreen. We’ve deprived ourselves of the sunshine to encourage our own bodies to make the Vitamin D we need.

It’s possible for even those who participate in outdoor activities to develop Vitamin D deficiencies. I was one of those individuals. For a quarter century I averaged four marathons a year — yet I was found to be Vitamin D deficient and took supplements for a few years.

I should qualify that. Most runners putting in that much mileage are at least tan, and very often look weather worn. I lived in foggy San Francisco and did almost all of my running in the predawn hours. At one point I thought that my claim to fame would be that I was the palest individual to have run 100 marathons.

My husband’s another example. For the last five years we’ve lived in Hawaii, and he spent much of his time swimming outside, riding a tractor, and clearing brush. But a few months ago his Vitamin D levels were found to be low. He also wears rash guards, a neck gaiter, gloves and sunscreen whenever he goes out, to protect against further skin cancers.

Skin in the game

Every dermatologist I’ve spoken with say that even brief exposure to UV light causes damage to skin. The longer UVA wavelengths penetrate more deeply, damaging connective tissue and leading to wrinkles and lost of elasticity. The UVB wavelengths damage the surface layers of living skin, causing sun burns and in the long term, skin cancers.

Most tanning beds expose individuals to more than ten times the amount of UV radiation than they would get from an equivalent time in bright sun. While there are UV-free tanning beds, they don’t help you tan unless you put some chemical glop on your skin. If you desire to injure your skin, then go ahead, use a tanning bed.

Despite our more sedentary, indoor lives, skin cancer rates are increasing — partly reflecting unprotected sun exposure decades earlier, when most individuals were less cautious about sun damage. The popularity of tanning beds many years ago also contributes to skin cancers now. Man-made deterioration of earth’s upper atmosphere has also allowed more UV light to rain down upon us. Finally, much more extensive screening for skin cancer has also increased the reported rates.

Despite the dermatologist’s claim that any sun exposure is damaging, I haven’t found evidence that small doses of sunshine — say several minutes a day — enough to replenish Vitamin D actually are causing a meaningful increase in skin damage. Our DNA accumulates mutations, including potentially cancer-causing mutations, all of the time, through errors in DNA replication, and the chemical environment within our cells.

To put it in perspective, a little over 10,000 Americans die from skin cancer each year, about 80% of which are melanomas. The vast majority of skin cancers, basal and squamous cell cancers, don’t kill people. Yet more than 200,000,000 Americans have insufficient levels of Vitamin D.

At least one dermatologist conceded to me that most individuals could safely tolerate, and would have a net health benefit, from several minutes of unfiltered sunshine daily. But he felt that if he told his patients that, it would be misinterpreted as a blanket encouragement to unrestricted exposure and tanning. Maybe he thought that human beauty and wisdom only run skin deep.

Let the sunshine in

Sunshine has benefits beyond promoting Vitamin D synthesis. As I’ve written about before, being outdoors has measurable mental and physical health benefits. For most people, spending additional time outside will also increase their level of physical activity, which has its own benefits.

If you thought sunshine laws referred only to government transparency and open meetings, a judge in California ruled in 2023 that inmates have a constitutional right to sunshine, although just 15 minutes a day was considered to be adequate. Many prisoners still don’t even receive that amount.

I guess I’ve spilled enough ink over spilt milk — or trying to get enough Vitamin D from supplements or dietary sources. If you’re Vitamin D levels are deficient or insufficient, it makes sense to do something about it, which might include taking supplements. But except for individuals with personal or family histories of melanomas or serious skin cancers, the information I’ve found suggests that most people could improve their health to a greater extent, and increase their Vitamin D levels, by spending a few more minutes each day exposed to unfiltered sunlight.

If I’m not promoting nuance, I’m probably creating new angst.

In April I wrote this article about oveporexton - and today (August 6, 2026) the FDA approved it for narcolepsy - which means it can also be used off label for ADHD.

Most of us have days when we feel mentally and physically depleted and it seems like we can’t fully wake up. Maybe we stayed up too late. Or drove ourselves way too hard to make a work deadline. Or have a bad cold or touch of the flu. Or long COVID, ADHD, depression, or some other ongoing condition that messes with our alertness and energy levels.

Feeling drained of energy and less than fully alert runs rampant in our society.

The healthiest approach is clearly to change behaviors to prevent feeling worn out, or to take steps that address the underlying problem.

But that often feels like too much. And hey, we’re tired anyway. So we often just swill a double espresso — or two — or reach for an energy drink. And many of us wonder, can’t we just take a pill for that?

There’s potentially a huge market for a brand new class of medications that are likely to become available later in 2026. Oveporexton, the first drug to bind to and activate orexin receptors in the brain — what pharmacologists call an orexin receptor agonist, is currently being evaluated for the treatment of narcolepsy. Narcolepsy is a rare condition marked by excessive daytime sleepiness, episodes of complete bodily collapse, and abnormalities of sleep at night or during daytime naps. But a medication that helps with narcolepsy may well also help millions of individuals with brain fog or who are otherwise wrung out, fatigued or hungover.

The orexin system in human brains is tiny, but extremely powerful. It has a major impact on neural circuits that control our lives, including regulating sleep, daytime arousal, eating, and even mood.

Before orexin receptor agonists reach your neighborhood or online pharmacy, it may help to know a little bit more about orexin, how orexin receptor agonists help with narcolepsy, and how safe or effective they might be for a number of everyday causes of daytime sleepiness and fatigue.

Double the pleasure

Orexin was discovered decades after neuroscientists knew about dopamine, serotonin and norepinephrine. Researchers first isolated and characterized orexin in 1998. Twice.

Two separate research groups studying appetite and food intake discovered a polypeptide neurotransmitter important for regulating this system. One group named the neurotransmitter orexin, for the Greek word for appetite. Anorexia, or having no appetite, comes from the same root.

The other group named their neurotransmitter hypocretin, because the neurons making it were located only in the hypothalamus and it appeared to resemble secretin, a polypeptide neurotransmitter made in the beginning of the small intestine that activates processes that help to neutralize the acidic digestive contents coming from the stomach.

It took many months for the groups to understand that orexin and hypocretin were the same molecule. And many more months to be aware that orexin wasn’t just involved in regulating appetite and eating, but also was centrally important in sleep regulation and other systems.

We now appreciate that there are actually two forms of orexin, imaginatively called orexin A and orexin B. (What hypocretin thought that one up?) Both orexin are synthesized from the same precursor mRNA, and share some similarities in structure.

The orexin are described as polypeptide neurotransmitters because they consist of chains of amino acids bonded together. They act upon receptors on the members of other neurons; when orexin binds to the receptor, it usually causes the neuron to fire.

Drugs that block orexin receptors are already available, including the medications Belsomra (suvorexant), Dayvigo (lemborexant), and Quvivik (daridorexant) that are used to treat insomnia. As I’ve written about previously, these medications appear to have advantages over other sleep medications, being less prone to promoting tolerance or addiction, and promoting sleep in more natural ways than do previous medications.

In addition, one of the most popular “brain boosting”drugs, Provigil (modafinil) appears to work, in part, by activating orexin neurons. The FDA approved modafinil to treat daytime sleepiness associated with narcolepsy, sleep apnea, and shift work, but it is widely used off label for additional conditions that cause sedation. Individuals also take it to enhance focus, concentration, and mental performance.

Although it has been available for more than thirty years, it remains unclear how exactly modafinil works. It is not a simple orexin receptor agonist, rather it indirectly activates orexin cells, as well as blocking dopamine reuptake and having actions on other neurotransmitter systems.

Orexin’s got you covered

Fewer than 80,000 neurons in humans make orexin, and they’re all located in the lateral hypothalamus and areas immediately adjacent. That represents less than one out of a million neurons in the brain, yet orexin is incredibly powerful because these cells project to a number of important brain regions, and modulate a number of other neurotransmitter systems, including:

Brainstem arousal centers

• noradrenergic cells in the locus ceruleus

• serotonin cells in the dorsal raphe

• histamine cells in the tuberomammillary nucleus

• acetylcholine cells in the pedunculopontoine tegmental nuclei

Limbic / emotional system

• amygdala

• bed nucleus of the stria terminals

Reward seeking and motivational circuits

• dopamine cells in the ventral tegmental area

• GABA cells in the nucleus accumbens

Executive and cognitive networks in the cortex

• hippocampus

• prefrontal cortex

• acetylcholine cells at the base of the forebrain

Hypothalamic centers regulating metabolism, appetite

• paraventricular nucleus

• dorsomedial nucleus

• arcuate nucleus

To further complicate matters, there are two separate orexin receptors, and no, they do NOT correspond to the two varieties of orexin. The orexin-1 receptor (OX1R) binds orexin A ten times more strongly than it does orexin B. But OX2R binds the orexin A and orexin B equally well.

While there is considerable overlap in the regions each system innervates, there are also distinctions. For example, the norepinephrine cells in the locus ceruleus contain almost exclusively OX1R, whereas the hypothalamic and tuberomammilary nuclei only contain OX2R.

To oversimplify, OX2R can be considered the system regulating arousal and wakefulness, with OX1R being more involved in the reward, motivation, feeding, metabolic and other functions. Oveporexton was chosen for exploration as an agent to treat narcolepsy because it binds specifically to, and activates OX2R.

Don’t fall asleep now

Within a year of the discovery of orexin, researchers who study sleep deciphered that orexin was intimately related to narcolepsy. Many mice, dogs, and humans with narcolepsy have a nearly complete absence of orexin neurons in their hypothalamus, and little to no orexin circulating in their brains. Injections of orexin could temporarily treat symptoms of narcolepsy.

Narcolepsy is characterized by five features:

• excessive daytime sleepiness

• disrupted night time sleep

• cataplexy, an abrupt loss of muscle tone while remaining awake

• sleep paralysis

• hallucinations upon falling asleep or awakening

Several of these symptoms involve the blurring or mixing of usually separate stages of sleep. In particular, the intrusion of REM sleep, when we are normally dreaming but our muscles are paralyzed, into wakeful states produces many of the distressing symptoms of narcolepsy.

Narcolepsy impairs people. The ongoing sleep deprivation, excessive daytime sleepiness, and intrusive episodes of loss of muscle function interfere with daily functioning and preclude many activities like driving a car. Narcolepsy also commonly evokes depression and anxiety.

Type 1 narcolepsy results from autoimmune destruction of orexin cells. While genetics contribute to those who are most at risk, if a parent has narcolepsy, there is only a 1–2% risk that their child will develop it. This is still considerably higher than the 0.04% risk of developing narcolepsy in the general population.

Dysfunction in other parts of the sleep regulating systems cause type 2 narcolepsy, which is less common than type 1. In type 2 narcolepsy, orexin levels are usually normal.

Orexin to the rexscue

About a decade ago, pharmaceutical companies began exploring narcolepsy treatment based on drugs that would activate OX2R. Takeda’s first two promising agents didn’t make it past preliminary stages of research. One required intravenous administration, which wasn’t considered a viable option for everyday treatment of narcolepsy. The second OX2R agonist was quite effective in alleviating narcolepsy when taken as a pill, but several patients in treatment trials developed liver toxicity.

This prompted Takeda to improve upon these earlier molecules. With oveporexton they succeeded in designing a drug that was at least ten times more potent than previous molecules in binding to OX2R, and at least so far, appears devoid of liver-damaging side effects.

Why all of this work to design an orexin receptor agonist? Couldn’t scientists just synthesize orexin in the laboratory for use as a medication? Polypeptides like orexin tend to be broken down into constituent amino acids by the digestive system. Even if it got into the bloodstream, orexins travel poorly across the blood brain barrier, and have fairly short half lives, further limiting the clinical utility of orexin in a pill.

As of April 2026, only the phase 2 trial of oveproexton has been published. This study included 90 patients, aged 18–70, all of whom had type 1 narcolepsy. After seven weeks of washout from any previous narcolepsy medications, the researchers randomly assigned subjects to one of five treatment groups. During the eight weeks of treatment, subjects received two pills each morning, at 8:00 am and 11:00 am. Depending on the group they were assigned to, subjects received either placebo, or a total daily dose of oveporexton that ranged from 1 to 7 mg.

The findings from the study were strongly positive. Compared to the placebo group, those receiving oveporexton displayed:

• increased ability to stay awake in a dark room

• better sleep at night

• a longer time to the first REM episode of sleep

• substantially fewer episodes of cataplexy

• reductions in patient-rated narcolepsy symptoms.

Oveporexton worked quickly and had a moderate to strong effect on improving these variables. Notably, results were statically and clinically better than in previous studies with other drugs approved for treating narcolepsy, including modafinil, methylphenidate, and solriamfetol (Sunosi).

Takeda has announced that the phase 3 studies, with a larger number of subjects and a narrower range of dosages, are consistent with the phase 2 study and confirm the efficacy of oveporexton for treating narcolepsy.

A further analysis of the data from the phase 2 study found that oveporexton improved attention, memory, and executive function over the eight week study period. These cognitive benefits are particularly attractive to individuals who may be tempted to try oveporexton for conditions other than narcolepsy. However, the phase 2 study was not designed to reveal whether the cognitive enhancement resulted from improved sleeping, or whether it was due to the influence of orexin neurons on other circuits in the brain.

Oveporexton wasn’t free of side effects, but they tended to be mild and did not cause subjects to abandon the medication. Almost half of the subjects had insomnia, which usually resolved within a week. About a third of subjects had troubles with increased frequency of urination, a third had troubles with increased urgency of urination, and a third had excessive salivation.

These side effects on the urinary tract and on salivation are likely to derive from orexin’s effects on acetylcholine and norepinephrine systems rather than a direct action of orexin. Rats don’t appear to salivate more when they’re treated with oveporexton. It’s not clear how often these side effects may persist, or how best to avoid them, or whether in the long term they would outweigh the benefits of taking the medication.

A rousing finale

Takeda has submitted the necessary phase 3 studies for approval of oveporexton and expects that the FDA will approve the drug for narcolepsy treatment in the third quarter of 2026. Depending on cost and insurance coverage, narcolepsy type 1 patients are likely to benefit quickly from having access to a medication that appears both safer and more effective than existing treatments.

Existing treatments for narcolepsy increase heart rate and blood pressure, which oveporexton does not appear to do. Many of the existing treatments have the potential to cause agitation and anxiety, and are potentially addictive, none of which have been shown to be risks with oveproexton.

Other pharmaceutical companies are currently developing their own OX2R agonists for narcolepsy treatment.

The market for narcolepsy itself is small, but it is likely that some pharmaceutical companies may envision wider usage of OX2R agonists, because they are likely to be effective in helping people stay awake under a much broader range of conditions. As I’ve written about previously, the FDA has somewhat relaxed standards for approval for “orphan drugs” that treat rare conditions such as narcolepsy. Companies can later seek additional approval for treating other conditions, or doctors can legally and ethically prescribe the medications off-label wherever they deem them appropriate.

In the week since I started writing this article, Eli Lilly has agreed to pay more than six billion dollars for the pharmaceutical company, Centessa. Centessa has not brought any products yet to market, but is developing at least two OX2R agents for treating narcolepsy and promoting daytime wakefulness. Companies don’t invest funds like that unless they expect big profits in the future.

While it makes far more sense to address the underlying causes of low energy, impaired alertness and fatigue, in the future we’re likely to see OX2R agonists used for sleep apnea, sleep deprivation, ADHD, and a number of other conditions.

Recently neuroscientist Mohammad Dawood Rahimi of the Free University of Berlin has contributed to the discussion of Attention Deficit Hyperactivity Disorder (ADHD) by introducing the concept of Energy Deficit Hyperactivity Disorder (EDHD). EDHD directs us to think of the problems associated with ADHD as being due to insufficient energy delivery to critical brain circuits, rather than anything being intrinsically wrong with those networks themselves.

Officially, ADHD is a list of symptoms — normal behaviors carried to excess and causing distress and dysfunction. Increasing numbers of individuals endorse ADHD symptoms, such as severe distractibility, troubles concentrating, avoidance of difficult tasks, fidgeting and impulsivity. As many as a quarter of American adults wonder if they have ADHD.

But for years now, many researchers, patients, and clinicians have conceptualized ADHD somewhat differently. A view promoted by articulate psychologists like Thomas Brown and Russell Barkley is that ADHD is not as a checklist of disparate symptoms, but rather as a condition in which executive functions — how the brain processes and manages information — are wired differently.

Rahimi repeatedly and explicitly states that he is not trying to change the clinical definition of ADHD or its name. Yet within weeks of the publication of his paper, online discussions have focused on whether individuals have EDHD rather than ADHD.

An evaluation of the EDHD framework requires an exploration of what Rahimi has proposed, as well as how those ideas and labels are resonating in the real world.

The broken system

We can debate whether anyone’s brain is truly “broken” but there’s no denying that our current system for diagnosing and labeling psychiatric conditions is broken.

Despite its name, people with ADHD don’t have a deficit of attention. Instead, they have challenges controlling and directing attention. ADHD symptoms aren’t limited to attention alone, but also include difficulties with other executive functions including organizing and prioritizing tasks, resisting impulses, and regulating restless behavior.

The formal Diagnostic and Statistical Manual (DSM) criteria also omits mention of several symptoms prevalent among those with ADHD, such as emotional dysregulation, circadian rhythm and sleep disturbances, and difficulties with time awareness and management.

One important critique of the DSM approach to ADHD comes from those who classify ADHD as a form of neurodivergence — as a different style of processing information rather than one that is inherently defective. This is why I refer to ADHD as a condition, rather than a disease or disorder.

The neurodivergent approach has prompted pushback. Some feel that it trivializes a condition which is potentially disabling and sometimes lethal. Others worry that if ADHD is no longer considered a disorder then health insurance companies won’t cover its treatment.

What does EDHD add?

Rahimi proposes that ADHD isn’t primarily due to miswired executive function circuits, but rather is a mismatch between energy availability and demands. The performance of neurons and their networks deteriorates when they don’t have enough energy. ADHD is thus framed as a state-dependent condition rather than a permanent deficit. The EDHD model helps explain why the behavior of individuals with ADHD is classically so consistently inconsistent, with so much day to day and a task to task variability.

EDHD encourages researchers to consider a range of factors affecting the energy supply to neurons, including the efficiency of mitochondria; the availability of ATP, the chemical source of cellular energy; the demands of neurotransmission and making synaptic connections; and the costs of inflammatory and oxidative damage. EDHD also focuses on how rest, sleep, and circadian factors contribute to the recovery and availability of energy supplies.

Under the EDHD framework, behaviors that are viewed as symptoms of ADHD in the DSM model, such as hyperactivity, task-switching, impulsivity, and avoidance, are viewed as responses to limited energy stores, and not necessarily pathological. EDHD also acknowledges that while many of these ADHD behaviors are adaptive in the short term, to address energy shortages, that many of them actually result in long term further draining and depletion of neural energy stores.

The EDHD approach appears to align with Yale psychiatrist Chris Palmer’s thesis that energy deficiencies underly mental health conditions, and that ketogenic diets which address the brain energy shortages may be effective treatment for many individuals.

Recent research that stimulant medications for ADHD work more strongly on arousal networks than on pathways devoted to attention, also supports an emphasis on energy concerns rather than on defective executive function circuitry.

Objections to the model

Currently EDHD is more a framework for studying ADHD rather than a set of specific proposals about the nature of ADHD. Although in many sections of his 22,978 word treatise Rahimi “foregrounds” energy sufficiency as the primary contributor to ADHD, he backtracks in other sections by stating “EDHD does not posit metabolic dysfunction as a universal, primary, or sufficient cause of ADHD-related phenomena.” But if energy deficiencies aren’t the major contributor to ADHD, what is the purpose of providing the label EDHD? Why not just write an article about ADHD stressing the importance of energy availability to neurons?

EDHD also seems to ignore a wealth of data indicating that many individuals with ADHD display disrupted executive function circuitry. This includes numerous studies showing different, aberrant wiring patterns in the prefrontal cortex of those with ADHD, as well as research demonstrating that prenatal exposure to toxins such as lead or unusual levels of thyroid hormone, increase the likelihood of developing ADHD.

Clinically, the EDHD claim that in ADHD executive function circuits are intact, but just get fatigued and dysfunctional at times, doesn’t match what many of my patients say they experience. They talk about feeling like their brains always perform differently than their peers’. Even if there are fluctuations during the day, they constantly feel that their thoughts are nonlinear, or have impulses to act or speak out, or that 237 tidbits of interesting, distracting information are bouncing around inside their skull.

They always feel neurodivergent. Even when they accomplish goals they feel they achieved their goals via unusual pathways.

On the surface, EDHD also doesn’t seem to align with the most common pattern of ADHD performance — of brains working worst in the morning (when well rested and energy supplies should be robust) and best late at night (when on average energy is most likely to be more depleted).

Proponents claim that EDHD explains hyperfocus — states of complete absorption in a topic, often for hours at a time, common for many people with ADHD. Hyperfocus is energy intensive, but in EDHD hyperfocus somehow also automatically generates the energy to sustain itself. To me this sounds like transporting a perpetual energy device from science fiction into the brain.

EDHD seems to minimize the importance of motivation in ADHD. One apt description of ADHD brains is that they are driven by interest not importance. A kid who loves math can focus intently on multiplication problems in the classroom, but is turned off and distracted during language lessons. But it doesn’t appear that she gave up in Spanish class because her energy became depleted, rather she was bored from beginning without even engaging with the task.

Some of my criticisms of EDHD are clearly embedded in how I’ve thought about and worked with individuals with ADHD for more than thirty years. My interactions with my patients and their own perceptions of themselves have been shaped by the labels and frameworks we’ve been using for the past several decades. So it’s possible that I’m overly focused or stuck on framing ADHD in terms of deficits in executive functions. I might be rating interest and motivation as at least as important as energy supplies in contributing to ADHD symptoms because I’m stuck seeing what I already believe.

Reducing Stigma?

Although Rahimi declares EDHD to be a research protocol, not a clinical tool, he also claims several times that EDHD destigmatizes ADHD behavior by shifting the focus from behavioral willpower to biological capacity. Which means he is acknowledging that many individuals will likely use the EDHD title in a clinical sense. I fear that many, upon hearing EDHD, will resort to the old trope that those with ADHD are simply being lazy or have “low energy”. The label will prime them to believe that a good night’s sleep or a nutritious meal should be sufficient to restore an EDHD brain to a fully functional state.

From my perspective, a neurodivergent perspective that localizes the differences between those with ADHD and those without to the domain of executive functions seems less pejorative than the EDHD label.

Furthermore, I think that EDHD will blur the distinctions between people with “low energy” due to depression, thyroid problems, autoimmune problems, and chronic infections and those with ADHD. Do all of these individuals have some form of EDHD? If Palmer is right and brain energy depletion is responsible for schizophrenia and depression and anxiety disorders, are all of these forms of EDHD?

Another level of potential confusion, and one I bring up not just to get a rise out of readers, is that “ED” is already widely used to refer to erectile dysfunction. I don’t think we want anybody to be worrying about having erectile dysfunction hyperactivity disorder.

Finally, the two most stigmatizing words of the ADHD label, “deficit” and “disorder” remain intact in EDHD. Perhaps if the value of the EDHD model is demonstrated over time, we will start to refer to those with ADHD as having Neuro-energy Asymmetry Temperament. Now that would be NEAT!

Rahimi deserves praise for directing more attention to the mismatch between energy supplies and demands that can contribute to ADHD symptoms. But I’m not sure I have the energy to combat the confusion and misdirection that will be created should EDHD come into widespread use.

If I’m not promoting nuance, I’m probably creating new angst.

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Lots of people — up to a quarter of American adults — worry that they have Attention Deficit Hyperactivity Disorder (ADHD). At the same time there’s intense concern that doctors over diagnose ADHD and prescribe powerful stimulant medications too frequently.

However, there’s compelling evidence that we’re still missing ADHD when it’s present. One recent study found that one third of individuals hospitalized after car accidents had ADHD which was previously unrecognized.

One challenge in identifying ADHD is that all of the behaviors characteristic of ADHD are also behaviors of people without the condition. To make a diagnosis of ADHD these actions must be excessive for one’s age and culture and lead to distress and dysfunction. But an additional factor leading to difficulty in diagnosing ADHD is that it exists along a spectrum; it’s a condition that varies along a continuum.

The ADHD spectrum dispels the notion that ADHD is a simple binary — that you either have it or you don’t. ADHD is more complex than that, and it behooves most people who are alive right now to understand some of that intricacy. If you think that ADHD doesn’t affect you, you’re probably wrong: a multitude of forces (internet immersion, poor sleep, long COVID, and many more) are pushing our brains further along the ADHD spectrum. Even if you’ve avoided many of these forces in your own life, you’re interacting with other people who are becoming more ADHD-like year by year.

Our ADHD World

The ADHD spectrum includes people who show:

• very few or no behaviors of ADHD

• some problems with forgetfulness, distraction, and impulsivity

• subthreshold levels of ADHD

• full clinical ADHD

Some psychologists use the terms subclinical or subsyndromal ADHD for individuals with multiple symptoms of ADHD that don’t quite meet the formal criteria for an ADHD diagnosis. However, since these individuals do have symptoms of ADHD, which often do reach clinical significance, I’ll be sticking with the more accurate term subthreshold ADHD.

Demarcations between these categories on the ADHD spectrum are imprecise and somewhat arbitrary. Even if our criteria are explicit and objective, people themselves can change over time.

Twofold variation

The ADHD spectrum embraces two realities: that ADHD symptoms can vary in intensity or severity both within an individual, and from person to person, and that an individual may primarily manifest some subset of ADHD symptoms and not others.

The current standardized diagnostic criteria for ADHD include nine inattentive symptoms and nine hyperactive / impulsive symptoms. For clinical ADHD, an individual over the age of 17 needs to persistently display only five of these symptoms over the course of the past six months. The symptoms need to have begun before age 12 and not be attributable to other conditions. This means that there are 116,200 different possible combinations of symptoms individuals can have to meet the basic ADHD criteria!

No wonder individuals with ADHD don’t all look or act alike. But more fundamentally, those with ADHD don’t all look or act alike because it’s just one aspect, albeit an important one, of any individual.

Measuring ADHD

It’s easy to understand that two people with the same condition may be affected to different extents. Not only does each person have other strengths and vulnerabilities that shape their ADHD thought patterns and behaviors, but ADHD symptoms can vary in intensity or severity. However, as with other mental health conditions, we have no simple tool for accurately measuring the presence, much less the intensity, of ADHD symptoms; we have no accurate yardstick for ADHDness.

Increasingly, the mental health community views ADHD as a form of neurodivergence, and consistent with that approach, “intensity”, rather than “severity” is used to describe the strength or prominence of ADHD-driven behaviors and traits.

But almost always, researchers and clinicians don’t measure the intensity of ADHD symptoms, instead they record proxy measures: the number of symptoms or the frequency of symptoms. Both of these measures have shortcomings, which diminishes the meaningfulness of how we distinguish clinical ADHD from subthreshold ADHD.

We make mental health diagnoses and try to assess the intensity of symptoms for the same reasons we make diagnoses in the rest of medicine: to understand what’s going on, to provide general predictions for an individual’s future, and to guide the selection of treatments likely to alleviate symptoms. We try to establish categories such that those who meet the criteria experience some impairment in functioning, and those not in the category are less likely to do so.

Meta-analyses show that subthreshold ADHD impairs educational and financial success, is associated with higher rates of incarceration, and leads to problems with physical health. Although these connections aren’t as strong as for clinical ADHD, those with subthreshold ADHD do not fair as well in life as those who are not on the ADHD spectrum. Those with subthreshold ADHD are also more likely to have other mental health conditions, such as depression or anxiety, and to display other neurodivergent tendencies, such as autism, left-handedness, and minoritized sexual orientation and gender identities.

Number of symptoms

It seems logical that the greater the number of the 18 ADHD diagnostic symptoms an individual displays, the more intense their ADHD. But there are major problems with the standard list of 18 symptoms, which were initially compiled for the diagnosis of children with ADHD, and only later modified for adults.

One of the most widely accepted current conceptualizations of ADHD is that it represents unusual patterns of activation and performance of executive function circuits in the prefrontal cortex. Executive functions describe how brains organize and process information, and include capabilities such as directing, sustaining and switching attention, working memory, impulse control, and emotion regulation.

The 18 symptoms used to make ADHD diagnoses do not show a one to one correspondence with executive functions. To begin with, the list of 18 symptoms contains multiple highly overlapping measures of hyperactivity. If you meet criteria for one of these symptoms related to excessive movement, you’re very likely to meet it for a few others. On conventional ADHD rating scales, someone meeting criteria for four symptoms of hyperactivity scores as high as someone meeting criteria for four very disparate symptoms of ADHD.

The second problem is that several of the ADHD diagnostic criteria cover a number of separate executive functions. For example one ADHD symptom is “difficulty organizing tasks and activities (poor time management, disorganized work, misses deadlines)” which could be met with atypical executive functioning in sequencing tasks (keeping things in order), prioritizing (choosing which to do first), time perception, distractibility (staying on task), or working memory (keeping items in mind). Deficits in five or six areas of functioning might result in meeting the same, single diagnostic criteria, again calling into question whether the number of designated symptoms is a faithful measure of ADHD intensity.

Thirdly, the ADHD criteria omit or stint on several symptoms known to be commonly present in ADHD. The list contains no mention of emotional dysregulation. None directly addresses that those with ADHD tend not to just manage time differently, but to perceive it differently. Being late is one of the most common and socially disruptive features of ADHD, but is only indirectly addressed under “poor time management.” This means that there may be no way to tally some of the symptoms that contribute strongly to someone’s presentation of ADHD.

Symptom counting is a fundamental element of determining whether one has clinical ADHD — as an adult you need to have at least five (decreased from six prior to 2013). Most of the competing definitions for subthreshold ADHD also rely on counting symptoms. Yet counting the number of officially sanctioned ADHD symptoms is only a crude approximation of ADHD intensity.

Frequency of symptoms

An alternative to counting the number of symptoms as a way to measure ADHD intensity is to determine how often the symptoms are displayed. One of the most commonly used scales for measuring ADHD, the Adult ADHD Self-Report Scale (ASRS) uses frequency as a way to assess how strongly someone is impacted by their ADHD. Specifically, it asks whether, over the last six months, the symptom occurred:

• never

• rarely

• sometimes

• often

• very often

The scale tallies a higher score based on the frequency with which the symptom occurs.

While frequency offers the illusion of objectivity, it’s problematic in a few ways. One is that whether one employs a self-report measure like the ASRS, or an assessment by an outside observer, it assumes that the person doing the evaluating can accurately perceive and remember behaviors over a fairly long time span.

Secondly, measuring frequency conflates how often a behavior occurs with how disruptive or disturbing it is. Is being 12 minutes late every day for work really five times worse than being an hour late once a week? Is losing your eyeglasses several times a day really more problematic than forgetting your cellphone when you go on a trip? Frequency only measures one aspect of the potential impact of a behavior.

Fluctuations in symptoms

Perhaps the biggest problem in using frequency of behaviors to measure ADHD intensity is that ADHD itself is characterized by being consistently inconsistent. Within any individual ADHD symptoms vary a great deal. ADHD symptoms fluctuate based on:

• task

• time of day

• daily variation

• longer term trajectories.

One description of ADHD is that “Typical brains are importance driven, while ADHD brains are interest driven.” An individual with ADHD knows they have to take out the trash, turn in their report, brush their teeth, or thank their grandmother for a gift, but if a more interesting option is before them, they tend to neglect what’s important and engage in the interesting. Someone with ADHD engaged in tasks they find interesting and motivating is likely to display many fewer instances of ADHD-like behavior than when faced with tasks or opportunities that are either too boring or too challenging.

Some have suggested that the energy available to neurons is a primary factor driving this task to task fluctuation in apparent ADHD symptoms. But from my clinical perspective, motivation seems to be the driving factor, with energy availability simply being one mechanism through which motivation may affect the functioning of brain circuits.

Circadian rhythms influence all bodily functions, including those related to brain performance. Those with ADHD tend to not just show delayed sleep-wake cycles, but have a strong likelihood of feeling groggy and dysfunctional early in the morning, and performing more effectively and fluidly late in the day.

Most of us have days when we wake up feeling positive and powerful and other days when we feel off, with low energy and muddled thoughts. Such daily variations are often more extreme in those with ADHD. Factors that can profoundly alter day-to-day performance include the quality of sleep the night before, whether or not someone took their medications, as well as exercise, diet, and meditation. But often for those with ADHD it remains opaque why one day is tremendous and another completely sucks.

These short term variations in functioning make it more challenging to evaluate the intensity of ADHD in any individual. When we use frequency of symptoms to assess ADHD intensity, are we averaging the good hours, the bad ones, or all of them, for a composite score? Are we including the up days as well as the down days?

As with number of symptoms, frequency of symptoms is at best a crude measure of ADHD intensity.

Long term problems with frequency

Although some diagnostic systems suggest and impose that someone either has or does not have ADHD, and that by adulthood this is a relatively stable condition, reality doesn’t concur. A long appreciated clinical observation is that individuals often show up for assessment of and treatment for ADHD at times of transition — particularly when either demands have increased, or external sources of structure and support have decreased. Common examples of this include switching from middle school to high school, going off to college, or entry into the work force. Often the skills and strengths that someone on the ADHD spectrum previously relied on are insufficient for the new challenges.

Movement along the ADHD spectrum can occur in both directions. Longitudinal studies show that many individuals who meet criteria for clinical ADHD at one point in time, fit into a subthreshold ADHD category at a later point. And many who have subthreshold ADHD eventually fulfill clinical criteria for the condition.

Some of the reason for movement along the ADHD spectrum appears to be the situational and transitional factors mentioned above. But we also have growing evidence that a number of factors in the exposome — the accumulated environmental, lifestyle, social and psychological factors we’re exposed to, can alter our brains and the presence of ADHD symptoms. Many of these factors, such as head trauma, lead or plastic exposure, immersion in social media/online life, lack of exercise, or long COVID appear to degrade the workings of our prefrontal cortex, disrupting executive functions, and pushing many brains further along the spectrum of ADHD intensity.

Because life is dynamic, not static, the intensity of ADHD symptoms for any individual can vary over time.

Where to draw the line

For any human trait existing along a spectrum it can be challenging to draw a line demarcating what’s intense or extreme enough to warrant special designation. A spectrum means there are no hard boundaries.

This is even true for a variables which are objective and simply measured, like height. Who do we consider to be tall? We could use statistical criteria like being two standard deviations above the average which would mean about 6’3” or taller. But often we create categorical decisions based on idiosyncratic beliefs. For example, in my younger years I was 5’12”, or slightly above average. But my husband, seven inches shorter, still refers to me as “freakishly tall”.

Decisions about whether a trait is extreme or pathological often become tied to social norms and expectations, as well as being mired in our individual interpretations. For traits that exist along a spectrum and are important to health and well-being, such as blood pressure, doctors attempt to draw the line around what is unhealthy based on

research that shows considerable risk associated with levels above a certain value. But as we’ve seen with blood pressure, those cut-off levels can change from year to year, as new information comes in.

Observer bias is particular relevant when assessing the intensity of ADHD. Information gathered by self report, or by an evaluator listening to what an individual reports, is filtered through the neuro-atypical ADHD brain of that individual. Making sure definitions and language are in alignment is crucial to making accurate assessments.

In my thirty plus years of clinical experience I’ve noted that many individuals with ADHD have rather porous definitions of the two L-words: “late” and “lost”.

My patient, Bill, had just finished saying that he was never late for work. I pointed out that just last week he had reported that his boss had been ready to fire him for being late. “Oh, I was two hours late that day.” I then asked him when he usually showed up for work. “9:15, 9:20, something like that.” Finally I asked when his boss expected him to be at work. “That’s 9:00.” In Bill’s mind fifteen or twenty minutes late wasn’t really late, even though, or maybe especially because, he was that tardy virtually every day.

Similarly, during evaluations for ADHD evaluations individuals often deny that they regularly lose things. After Katherine said “No, I don’t lose things.” I pointed out that she had just mentioned often misplacing her glasses. “Oh, I don’t lose them. I just can’t find them. Sometimes for days.” Some individuals with ADHD seem to have a quantum mechanical concept of existence, kind of like Schrödinger’s cat, which can be either alive or dead at the same time. Objects that can’t be located aren’t “lost”. Perhaps an item has to cease existence for eternity in order to be considered lost.

It’s often hard to rank data that is qualitative rather than quantitative, a problem pervasive in mental health assessments, not just in ADHD assessments. Even if we can rank one action as more extreme than another when they’re directly compared to each other, in the absence of reference points it can be tricky to determine whether a behavior is problematic enough to be classed as a symptom.

Here’s an example that focuses on assessing the intensity/severity of emotional dysregulation. Let’s say you’re at a company meeting and your manager promises the team the unachievable goal that you’ll deliver functional and bug-free work for your project by Friday.

Your possible responses might include:

• Sitting quietly, thinking “Why did she say that? It’s not possible.”

• Silently fuming, but breathing heavily, with your nostrils flaring.

• Yelling “ARRRGH” and slapping your forehead with both hands.

• Screaming “You f*ing moron!” and flipping over the conference table as you storm out the door.

Most of us would rank those scenarios as increasing in their intensity of emotional dysregulation. But in a situation where we aren’t directly comparing alternative responses, which of these represent intense or extreme responses?

Neither counting symptoms nor the frequency of symptoms represent ideal ways to capture the intensity of an individual’s ADHD symptoms. However, I don’t have a good answer regarding what might serve as better standards. Perhaps with modern technology continually monitoring us, and AI calculating the rarity of certain behaviors, we might come up with more quantifiable and representative measures. But so far, AI is far more adept at assessing and dealing with the ordinary than with the outliers.

Additional issues

Some claim that the acknowledgement that ADHD occurs on a spectrum means that we are pathologizing normal behavior. However, the definition of ADHD embeds a measure of distress and dysfunction, which should be reserved for behaviors beyond what is usual or normal. Thresholds should be established that are high enough that we’re not characterizing everyday inefficiency or unhappiness into a condition. The lower a threshold is set, the harder it is to distinguish between those with and without the condition. A low threshold also makes it harder to differentiate ADHD from other conditions, like depression, or anxiety, that may share some symptoms.

Others object that the incredible variation encompassed by the ADHD spectrum shows the term “ADHD” is meaningless, and that we’ve lumped together a collection of very different conditions. One origin of this objection arises from the paradox that each of us are simultaneously individuals as well as being human beings. Each of us is always like others and unique in our own way.

I believe that the ADHD label identifies meaningful commonalities among individuals. Thousands of studies support that as a group, those with ADHD show patterns of neurocircuitry and neurochemistry that differ from those without ADHD. In addition, a multitude of treatments, including medications, brain modulators, and behavioral and psychotherapies are effective in specifically treating ADHD symptoms. While there is certainly room for improvement in assessing and measuring ADHD, the diagnostic label has provided real life value to millions.

Rainbows, the embodiment of the visual spectrum of light, are incorporated into one of the international symbols for ADHD. Whether or not there’s a pot of gold at the end of the current ADHD spectrum, maybe Kermit the Frog had it right when he sang in the Rainbow Connection that it was wrong to think that “Rainbows are visions, but only illusions.” We’re all connected.

If I’m not promoting nuance, I’m probably creating new angst.

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Millions of individuals worldwide have taken reboxetine, but most Americans have never heard of it. Thirty years ago it was poised to become the first norepinephrine-reuptake inhibitor (NRI) antidepressant. But the FDA reversed itself, rejecting the drug. Now, in July of 2026, the FDA has changed its mind again, strongly signaling that within a year it will finally approve Axsome Therapeutic’s fast-tracked New Drug Application for reboxetine.

Why has reboxetine faced such changes in fortune?

A different norepinephrine reuptake inhibitor, atomoxetine (Strattera), was approved in the US in 2002 — and is now approaching annual worldwide sales of a billion dollars a year. Atomoxetine is used to treat ADHD, not depression. Is reboxetine poised to break into the lucrative ADHD market, or the even larger antidepressant market?

However, Axsome isn’t seeking approval of reboxetine as an antidepressant or an ADHD treatment. Instead, it has applied for using reboxetine to treat narcolepsy — a rare condition characterized by abrupt bouts of daytime sleep.

Is Axsome simply reboxing reboxetine to finally access the US market? Some contend that reboxetine is a completely ineffective drug. Others feel that it was prematurely rejected by the FDA, and that it might help not just individuals with narcolepsy, ADHD, or depression, but schizophrenia, bulimia, panic, and even Alzheimer’s.

To help understand what’s going on, and whether reboxetine might help you should it be approved in the coming year, I’m going to guide you through some of the research. This will include examining the significance of medications that bind strongly to some neurotransmitter receptors and transporters, and not to others.

What is reboxetine?

Reboxetine’s name refers to its structure, with “-oxetine” indicating that its shape bears a resemblance to the serotonin specific reuptake inhibitor(SSRI) fluoxetine, or Prozac. It’s not clear whether reboxetine was just arbitrarily assigned the “reb” prefix, or whether it was considered a rebellion against all of the previous serotonin-focused antidepressants. Certainly reboxetine is snappier than its chemical name of 2-(2-ethoxyphenoxy)-2-phenylmorpholine. But maybe a prophetic pharmaceutical proprietor wasn’t sure which box to put reboxetine into in order to market it to consumers.

Reboxetine was developed by Farmitalia, an Italian pharmaceutical company, in 1984. Pharmacia bought out Farmitalia in 1993. I recall attending the American Psychiatric Association annual meeting several times in the mid-to-late 1990’s when a huge booth advertised the impending approval of reboxetine. Reboxetine was going to revolutionize antidepressant treatment, with its norepinephrine reuptake action and no meaningful effect on serotonin. Each year Pharmacia proclaimed that reboxetine would be available “Soon!”

In 1997 several European companies approved reboxetine to treat depression. Based on the same studies, the FDA provisionally approved reboxetine in 1999. But the FDA reversed that judgement in 2001 deeming reboxetine “not approvable” based on the available research being too insubstantive.

In 2003 Pfizer, one of the largest pharmaceutical companies in the world, acquired Pharmacia. Pfizer has continued to manufacture and market reboxetine throughout Europe. In 2020 Pfizer sold the US rights to the drug to Axsome, which has been pursuing approval of reboxetine for narcolepsy, and a variant of reboxetine for fibromyalgia.

For the orphans?

Axsome’s current application for reboxetine is actually for cataplexy, the sudden involuntary loss of muscle tone in alert individuals, which is one specific symptom of narcolepsy. Axiom’s reboxetine application is utilizing the Orphan Drug Act. As I’ve discussed before, the Orphan Drug Act is a more rapid, less burdensome, less expensive pathway for drug approval, designed to expedite availability of medications to treat conditions which have only small potential audiences.

But pharmaceutical companies can manipulate the process. Once a medication is approved by the FDA for one indication, doctors can prescribe it for any condition that it may plausibly treat.

More than 100 times as many individuals have ADHD than have narcolepsy. Even greater numbers of people deal with clinical depression. Should reboxetine be approved in the US, doctors will be able to prescribe it off-label for ADHD, depression, panic disorder, bulimia, schizophrenia, or even bulimia.

Very similar medications

Reboxetine and atomoxetine (Strattera) are very similar NRIs. Similar here refers not to chemical structure, but how a drug acts on the brain, and which receptors and transporter molecules it binds to. For almost seven years, Strattera was the only non-stimulant medication approved to treat ADHD.

Both drugs bind tightly to and block the norepinephrine transporter (NET) and have minimal effects on the serotonin transporter (SERT). Usually, moments after a neuron fires and releases norepinephrine into the synaptic cleft, the NET pulls the norepinephrine back into the cell that released it, inactivating the norepinephrine message. A NET blocker, also called a norepinephrine reuptake-inhibitor (NRI), prevents this action, allowing norepinephrine to last longer in the synapse, and have a longer, stronger impact on the receiving neuron.

The table below compares the NRI reboxetine to atomoxetine and several other medications that are primarily used as antidepressants. The numbers here are binding affinities (Ki), specifically inhibitory binding affinities, or the amount of drug needed to bind to and block half of the receptors. A smaller number means much more potent binding; only a tiny amount is needed to block half the receptors.

Many of the Ki are provided as ranges, rather than a single number, because different labs performing slightly different assays with different equipment and materials can produce somewhat different binding affinities. It’s a good thing we’re not having any binding elections here. In the table I’ve compiled, all of the units are in nanomoles. Be careful when making comparisons between numbers derived from different articles, because some sources list binding affinities in micromoles which are 1000 times larger.

Reboxetine and atomoxetine bind about 100 times more strongly to NET than to SERT, which is why they are considered norepinephrine-specific. Their interaction with most other neurotransmitter systems is considered negligible. Both drugs do have weak ability to block G-protein-activated inwardly rectifying potassium channels (GIRK). Reboxetine also has weak antihistamine action, as well as weak action at the serotonin-2C receptor. Atomoxetine, but not reboxetine, has some ability to block NMDA glutamate receptors, which may be a small part of how atomoextine helps with ADHD.

Viloxazine, or Qelbree, was marketed as an antidepressant in Britain decades ago, and thought to be just an NRI. More recently it has been shown to be an effective agent for treating ADHD, and to have additional effects on specific serotonin receptors at therapeutic dosages.

In contrast, most of the serotonin and norepinephrine reuptake inhibitors (SNRI) (venlafaxine, desvenlafacine, duloxetine, and milnacipran) have robust effects on both receptors, and, with the exception of milnaciprina show significantly more potent blockage of serotonin than norepinephrine transporters.

A few older tricyclic antidepressants (TCAs) that are listed in the table above also are fairly specific for NET rather than SERT. However, the tricyclics are considered “messy” or non-specific drugs, since they also have effects on sodium channels, and receptors for histamine and muscarine that are often stronger than their effects on NET or SERT. The non-specific binding of the TCAs produces many of the side effects (sedation, weight gain, dizziness on standing, constipation, irregular heart rhythms) that are very commonly associated with these drugs.

Bupropion, or Wellbutrin, is considered to be a dopamine and norepinephrine reuptake inhibitor antidepressant and ADHD agent, with minimal impact on serotonin. Compared to the other medications in the table, bupropion’s absolute transporter binding is relatively weak, but it is still specific to dopamine and norepinephrine, not serotonin.

Nerds beware!

Some people like to geek out about binding constants, thinking that they will be able to foretell what impact a drug will have on human beings based on these objective, measurable numbers. While binding affinities can give us clues regarding in what ways a drug will affect humans, challenges arise that go beyond different labs obtaining somewhat different numbers based on different tissue samples and assay conditions.

One major problem is that neurotransmitters don’t work in isolation. Even if you had a drug which robustly affects serotonin, or dopamine, or norepinephrine, and had no direct impact on other receptors, boosting or suppressing activity in one of these systems is likely to have robust, rapid effects on other neurotransmitters. The brain is all about neurons interacting with each other. Serotonin, dopamine, and norepinephrine neurons modulate each other’s activity.

Furthermore, even if we have medications that bind very specifically, some of the transporters themselves are not that focused on a single job. For example, what we call the NET is capable of blocking the reuptake of not just norepinephrine but of dopamine as well. In fact, the NET is more potent at dopamine reuptake than is the DAT itself. In some parts of the prefrontal cortex, which are richer in NET than in DAT, dopamine is primarily regulated by NET rather than DAT.

This complexity is part of why we still need clinical trials of medications, to see if chemicals will live up to their theoretical potential for treating humans.

Antidepressant effects

How well does reboxetine work as an antidepressant? To begin with, it works really well — if you’re a rodent. Numerous studies in rat or mice models of depression find that reboxetine robustly changes depressive behaviors.

So how about in people? One early (2000) summary reviewed the rodent data and preliminary results in depressed humans and concluded that reboxetine was comparable to the most effective tricyclic and SSRI antidepressants, and had “an improved side-effect profile”.

But a meta-analysis a decade later (2009), that examined numerous studies on twelve relatively new antidepressants, found that reboxetine stood out for being indistinguishable from a placebo in terms of efficacy, while all of the other antidepressants outperformed a placebo. Furthermore, reboxetine was one of only three antidepressants that fared worse than the placebo group in terms of having more people leave the studies early. Reboxetine appeared to be relatively intolerable.

Skeptics of reboxetine often cite this 2009 study. They also point out that Pfizer has sat on the results of reboxetine antidepressant studies with outcomes that were even less impressive than the published data. Including the unpublished studies shows reboxetine to be even less effective than the 2009 meta-analysis suggests.

However, the same group of respected international researchers that conducted the 2009 meta- analysis conducted another, larger meta-analysis in 2018. This time they looked at 21 antidepressants, which included four times as many studies (522) and four times as many patients (116,477). This time reboxetine statistically outperformed a placebo for depression treatment, albeit being the least effective of the 21 medications. It also continued to be in the top three antidepressants for individuals dropping out of studies. To me it’s somewhat reassuring that looking at a greater number of studies improved, rather than flattening out, the signal that reboxetine is an effective antidepressant.

Side effect stories

Why did the early predictions of a beneficial side effect profile for reboxetine differ from the results of anti-depressant studies? I think that part of the answer is that among antidepressants norepinephrine side effects tend to differ from serotonin side effects. SSRIs fairly commonly cause sexual side effects, weight gain and emotional blunting, particularly at higher doses. Not only do NRIs tend to not produce these side effects, they can actually rescue individuals from these unwelcome outcomes. This is why SNRIs, which combine serotonin and norepinephrine reuptake blockade, tend to cause less severe sexual, weight, and emotional side effects than do SSRIs.

Researchers, clinicians, and patients in a serotonin dominated antidepressant world, expected that an NRI like reboxetine would bring a reprieve from the SSRI side effects, an expectation that is born out by the data. On the other hand, NRIs produce more norepinephrine-based side effects, which aren’t necessarily less tolerable or more dangerous than SSRI side effects, but are less familiar and less likely to be anticipated by subjects, which could contribute to subjects withdrawing prematurely from medication studies with NRI.

It’s also possible that expectations and experiences of medication tolerability are subtly shaped by some of the stereotypes, held by professionals and patients, regarding certain neurotransmitters. Norepinephrine is strongly linked with the fight or flight sympathetic nervous system, with arousal, and with being a potent disruptor of life as usual. In contrast serotonin is associated with contentment, soothing, and complacency. This may influence how individuals report what they are feeling and contribute to whether they remain in a study or not.

Common side effects for reboxetine (and other NRI) include:

• headache,

• insomnia

• decreased appetite

• dizziness

• dry mouth

• constipation, nausea

• excessive sweating

While it is uncommon, reboxetine can cause either insomnia or sedation. The sedation likely comes from reboxetine’s antihistamine action, which atomoxetine and other NRI lack. For unexplained reasons, most reboxetine studies failed to find elevations of blood pressure or heart rate that are common with other NRIs. This may suggest that dosages of reboxetine used in studies or clinically are at the weaker end of the therapeutic range, and thus may contribute to why it appears to be less effective as an antidepressant.

Reboxetine, with a half life of about twelve hours, lasts about twice as long as does atomoxetine. Reboxetine is broken down by P450 3A4 liver enzymes, so certain drugs, particularly antifungals, like ketoconazole, that interfere with 3A4 will increase blood levels of reboxetine.

Other uses

Due to its similarities to atomoxetine, reboxetine has been widely used for ADHD, although it has not been approved for that condition in any country. Studies of rodent models of ADHD demonstrate that reboxetine can reduce ADHD-like symptoms of hyperactivity, impulsivity, and inattention.

More than thirty published studies have found beneficial effects of reboxetine in the treatment of ADHD in children, adolescents and adults. But most of these studies were small, and only three of them were randomized controlled trials, the gold standard for clinical research. In most of the other studies, patients and doctors knew what treatment was being delivered, and there were no comparison placebo groups. A few studies documented that individuals who couldn’t tolerate stimulants could take doses of reboxetine that were effective in treating ADHD, and that reboxetine could reduce symptoms of anxiety and ADHD in individuals with both conditions.

Small numbers of studies have found positive results when treating the following conditions with reboxetine:

• bulimia

• panic disorder

• narcolepsy

• fibromyalgia

• schizophrenia

But in all cases, there is less evidence than there is for reboxetine in the treatment of depression or ADHD. We simply need larger, better studies to know how well reboxetine works.

Particularly interesting data in mice has found that reboxetine can both reduce the burden of amyloid plaque in the brain, and decrease the amount of tau tangles. The possibility that reboxetine can perform the same feat in individuals with Alzheimer’s tantalizes many researchers.

The FDA has strongly indicated that by the summer of 2027, reboxetine will become available in the US. After that, it’s hard to predict what will pop out of this jack-in-the-box medication. Will reboxetine become a jack of all trades, treating depression, ADHD, bulimia, fibromyalgia, and dementia, or will it be boxed in to just being used for narcolepsy with cataplexy?

I predict that given reboxetine’s low propensity for dangerous side effects, its similarity to atomoxetine, and its track record of world-wide use, that many Americans will at least try reboxetine for off label uses. It’s disappointing that we don’t have a larger body of research to clearly show how well it might work for all of these other conditions.

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If I’m not promoting nuance, I’m probably creating new angst.

HANSUAN FABREGAS / Pixabay

Many people are under the impression that Prozac and other serotonin specific reuptake inhibitors (SSRIs) stormed the antidepressant field and supplanted existing antidepressants in the 1980’s because these new medications were so much more effective. But SSRIs aren’t any more powerful in alleviating depression than their predecessors. On the other hand, their success wasn’t just the result of marketing hype. The SSRIs were genuinely safer and more convenient medications to prescribe.

Because the SSRIs’ biochemical actions in the brain were simple and specific, they avoided some very serious, and even lethal, side effects of the existing tricyclic antidepressants and monoamine oxidase inhibitors. But the SSRIs can cause side effects themselves.

A decade after the initial release of the SSRIs, dual acting serotonin and norepinephrine reuptake inhibitors (SNRIs) entered the field. Wasn’t this a step backward? Wouldn’t messing with two neurotransmitters cause twice as many side effects? Yet, for the most part, SNRIs worked at least as well as the SSRI, without increasing the side-effect burden.

Currently Otsuka Pharmaceuticals is developing centanafadine, a drug that is a dopamine, norepinephrine and serotonin reuptake inhibitor, for the treatment of depression, as well as for treating ADHD. Preliminary evidence suggests that this triple reuptake inhibitor may provide real benefits, while actually having fewer side effects than simpler medications.

Let’s explore why it is even plausible that disturbing the brain in multiple biochemical ways might result in fewer problems.

What reuptake inhibitors really do

Neurons communicate with each other using chemical signals called neurotransmitters. The signaling cell releases a packet of one type of neurotransmitter into the synaptic cleft, which is how neuroscientists refer to the tiny gap between two neurons. The neurotransmitter diffuses into the cleft, and binds to a specifically shaped receptor on the receiving neuron, thereby transferring the signal.

But if that were all that happened, the system would be locked “on”. The brain also needs a way to end the neurotransmitter’s signal. One way is for chemical enzymes in the synaptic cleft to chew up and destroy the neurotransmitter, halting its ability to signal the receiving cell.

Another method for ending the signal is for the neurotransmitter to diffuse back to the signaling cell, and then bind to a transporter molecule. Since nature likes to recycle, the transporter pulls the neurotransmitter back into the original signaling cell, so that it can be reused later.

Reuptake inhibitors block these transporter molecules, leaving the neurotransmitter available for a longer time in the cleft and able to bind to the receiving cell receptors.

Reuptake inhibitors don’t boost the amount of neurotransmitter released.

They allow the standard amount of neurotransmitter to exist for a longer time at the receiving cell, thereby increasing the length and strength of the signal.

An SSRI specifically allows serotonin to last longer at synaptic clefts throughout the brain and body. A triple reuptake inhibitor would allow serotonin, norepinephrine, and dopamine signals to be longer and therefore stronger.

We pay most attention to rare neurotransmitters

More than half the neurons in the brain signal excitatory messages using the neurotransmitter glutamate. Another third use the inhibitory neurotransmitter GABA. Yet the puny little dopamine and serotonin systems are far more widely known. Only about 1% of the brain’s neurons use dopamine, serotonin, or norepinephrine. (Norepinephrine may sound more familiar using its alternative name of noradrenaline.)

In part, dopamine and serotonin are famous because many of our medications work on these two neurotransmitters. They also have really good PR teams. But despite their size, dopamine, serotonin and norepinephrine are actually powerful systems because they start in tiny centers deep in the brain, and extend their terminal throughout the cortex and other brain regions to regulate and modify many kinds of neural circuits. This includes serotonin, dopamine, and norepinephrine pathways modulating and regulating each other.

Whose side are side effects on?

Reuptake inhibitors can have direct, immediate effects as well as indirect, delayed effects. The delayed effects usually occur from long term compensatory mechanisms, involving up or down regulation of receptor numbers; manufacturing of new proteins; and even generating new neurons. All of these processes take days to weeks to gear up and become effective.

Blocking dopamine reuptake quickly enhances arousal, attention, and awareness of rewards. Long term effects of dopamine reuptake include developing tolerance to previously rewarding stimuli.

Blocking serotonin often has immediate effects of inducing nausea, stifling libido, interfering with orgasms, and causing agitation. Reduction in depression and anxiety are usually long term, indirect effects of serotonin reuptake.

Side effects are just the label we put on any undesirable action of a medication, whether immediate, or indirect.

With the old tricyclic antidepressants, most of the undesirable and dangerous side effects were the result of the medications acting on neurotransmitter systems that weren’t relevant to the drugs’ beneficial effects. Actions on histamine receptors caused sedation and weight gain. Acetylcholine effects caused constipation and confusion. Dangerous heart arrhythmias came from interactions on sodium channels. The SSRIs don’t act on any of these systems, so they don’t produce those side effects.

In part, side effects are determined by which neurotransmitter systems are being affected.

The SNRI advantages

Psychiatry still lacks good ways to measure the severity of mental health conditions, or how well individuals are responding to treatment. For depression, our commonest yardsticks are lists of depressive symptoms, with responses registering as a tally of how many symptoms improve.

With such crude tools, many of our antidepressants look equally effective. SSRIs and SNRIs result in roughly similar rates of response. But some research indicates that treatment with an SNRI, compared to an SSRI, is more likely to result in complete resolution of depression. Clinically, this is what I have seen in many patients over the years.

Adding norepinephrine reuptake to serotonin reuptake does result in cardiovascular side effects that are usually mild. On average, blood pressure and heart rate increase by a few points, which is seldom medically significant. Over the years, I’ve had a few patients who needed to adjust their antihypertensive medications after starting an SNRI.

But SNRIs actually appear to lessen, or rescue many individuals from SSRI side effects. Weight gain is less likely. Emotional flattening, and apathy are both significantly less common when taking an SNRI.

SNRIs don’t provide a miracle combination — norepinephrine reuptake doesn’t eliminate all serotonergic side effects. Rates of nausea and of initial agitation appear similar for SSRI and SNRI. The likelihood of serotonin withdrawal from missing a dose or stopping cold turkey don’t seem diminished in SNRI compared to SSRI.

When medications alter a combination of neurotransmitters, side effects aren’t always additive.

Size of effect matters

SNRIs vary with regard to the relative strength of their actions on serotonin and norepinephrine. Venlafaxine (Effexor) possesses very strong serotonin reuptake action, duloxetine (Cymbalta) is fairly balanced between the two neurotransmitters, while milnacipran (Fetzima) acts more potentially on norepinephrine. This matters for side effects. For example, among SNRI, the stronger the norepinephrine action, the milder and less common are sexual side effects.

Strength of norepinephrine reuptake also seems to correlate with the likelihood of agitation and over arousal. It may seem nonsensical to simultaneously prescribe two SNRI, but I’ve worked with several individuals over the years who were exquisitely sensitive to serotonin and norepinephrine effects. They felt too flat on Cymbalta, but too revved on Fetzima alone. It took a combination of the two medications to create the perfect balance of serotonin and norepinephrine reuptake for these individuals.

Side effects depend on how strongly different neurotransmitter systems are affected.

The other dual reuptake inhibitors

A handful of medications are dopamine and norepinephrine reuptake inhibitors (DNRIs). Wellbutrin (bupropion) is FDA approved for depression, while Sunosi (solriamfetol) treats daytime sleepiness from narcolepsy or sleep apnea. Some of the side effects associated with serotonin reuptake, such as decreased libido, delayed orgasms, and weight gain, are avoided with these drugs.

Many sources refer to Ritalin (methylphenidate), a stimulant used for ADHD, as a DNRI. But methylphenidate has a risk for addiction, and perhaps psychosis, that isn’t apparent with Wellbutrin or Sunosi. Some evidence suggests that in addition to reuptake action, Ritalin may have additional action on specific dopamine receptors that contribute to these infrequent, but serious, side effects.

Triple the effects

Otsuka Pharmaceuticals has completed several Phase 3 studies with centanafadine. Phase 3 studies are the final testing required for approval,in which the drug is examined for benefits and side effects in several hundred patients, at multiple research sites. Such testing for centanafadine for ADHD treatment is further along than the testing for antidepressant action.

So far, centanafadine appears as effective for treating ADHD as other non-stimulants, which tend to be less potent than is the stimulant amphetamine (Adderall, Vyvanse and others.) In these studies, centanafdine has very low rates of side effects.

Research has only compared different doses of centanafadine to placebo; there are no head-to-head trials contrasting it to other medications. But psychiatrist Ann Childress and colleagues created a “matching-adjusted indirect comparison” study, where subjects that were comparable to those in the centanafadine studies, with respect to several variables, were selected from previously published studies of other medications.

Centanafadine was compared to three FDA approved treatments for ADHD, the stimulant Vyvanse, and the non-stimulants atomoxetine (Strattera) and viloxazine (Qelbree). In every single comparison, centanafadine had a statistically significant lower rate of each side effect than did the alternatives:

• appetite suppression (Vyvanse, Strattera)

• dry mouth (Vyvanse, Strattera)

• insomnia (Vyvanse, Qelbree)

• anxiety (Vyvanse)

• nausea (Vyvanse, Strattera, Qelbree)

• jitteriness (Vyvanse)

• diarrhea (Vyvanse)

• constipation (Qelbree)

• fatigue (Strattera, Qelbree)

• erectile dysfunction (Strattera)

• urinary hesitancy (Strattera)

For several of these potential side effects, centanafadine had a lower rate by 15% or more. Sometimes side effects become more apparent after medications have been on the market longer and used by more people, but even so, the low rates reported for centanafadine are strikingly impressive.

Rather than tripling the side effect profile, it seems that centanafadine interferes with three different reuptake inhibitors in ways that harmoniously tune the brain. Banging away on just one neurotransmitter can be more disruptive than collectively pushing on multiple systems that interact and regulate each other.

Cautionary tales

Several years ago, Sunovion Pharmaceuticals developed and was testing dasotraline, another triple reuptake inhibitor. Preliminary studies indicated that dasotraline effectively treated ADHD. I viewed numerous poster presentations at conferences extolling the virtues of the medication, amid promises that it would be released soon.

But after sinking millions of dollars into the project, Sunovion pulled the plug, with a rather opaque disclaimer that more studies would be needed for approval. Dasotraline’s side effects were markedly more abundant than centanafadine’s, but in particular, hallucinations and other psychotic experiences occurred with some individuals taking dasotraline. This again suggests that the drug’s action on dopamine was more than just a reuptake inhibitor.

Reassuringly so far, centenafadine seems to have a low likelihood of abuse potential or causing psychosis. Rodents find the drug aversive, not pleasurable. No reports of euphoria or craving have been elicited from human subjects on centenafadine.

Doctors have been using one triple reuptake inhibitor for decades. But it is only used as a topical anesthesia of the mucous membranes of the mouth, throat, and nose. It is allowed, but not explicitly approved, by the FDA, for these uses. That drug is cocaine. Cocaine has not been approved for other conditions because of its strong risk for addiction, and serious cardiac effects. In addition to being a triple uptake inhibitor, cocaine’s effects on additional dopamine receptors make it dangerous.

Who might centanafadine help?

For years most mental health research has only studies subjects with “clean” cases of a given condition. Studies of ADHD ruled out people with anxiety or depressive disorders. Subjects were ineligible for depression studies if they had a substance abuse problem, or PTSD.

The rationale for these exclusions was to simplify interpretation of research results. If a medication had a positive impact, it could clearly be assigned to helping with the targeted condition, rather than helping with a concurrent condition. This avoided problems like not knowing whether attention improved because core ADHD functions were enhanced, or because ongoing anxiety was reduced by the medication.

But in the real world, the majority of those with ADHD, depression, or anxiety have at least one other condition. Some of this co-occurrence is due to similar genes contributing to multiple conditions. Some we can attribute to one condition leading to another. For example, repeatedly ADHD-driven disasters at work, school, or social interactions makes depression or anxiety more likely.

Triple reuptake inhibitors are likely to be helpful to this with co-occurring conditions such as ADHD and depression, or ADHD and anxiety.

The addition of dopamine reuptake inhibition may also help those with residual apathy or cognitive problems after treating their depression with an SSRI or SNRI.

Is there an advantage of one drug having three actions, rather than combining medications, such as the very frequent use of Wellbutrin (dopamine and norepinephrine) with an SSRI? Some research indicates better compliance and results with fewer pills. But the current studies of centanafadine, which has a very short half life, have used twice a day dosing even with an extended release formulation. Centanafadine also locks patients into a fixed ratio of action on dopamine, serotonin and norepinephrine transporters, which may not be ideal for all patients.

Centanafidine doesn’t break new ground by engaging new neurotransmitter systems or mechanisms of action, but so far it looks likely to help many with ADHD, or depression, or both, and may simplify medication regimens, and be less likely than alternative medications to harm people.

Knowing what neurotransmitters are affected by an agent gives us some idea of what benefits and side effects to expect. But so far, even trained research pharmacologists and neuroscientists can’t accurately predict how well a new medication will work, or what harm it will cause, in a range of actual human patients.

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One of the challenges posed by ADHD is how to discuss your condition with family and friends and how much to reveal at school or in the workplace.

ADHD manifests differently in each individual. Even if your ADHD presents strongly, it’s only one aspect of your being. Other traits, strengths, propensities, and experiences shape who you are as a person. Each coming-out audience and situation is also unique. So there’s no single best way to share the awareness of your ADHD with others.

Despite all of the possible variations, some guidelines may help you think about and craft your coming out. These suggestions are based on my three decades working with neurodivergent individuals, and in particular from helping those with ADHD, or who are LGBTQ, share sensitive parts of their identities with important people in their lives.

Even if, in ADHD fashion, you blurted out the news to everyone nearby as soon as you learned you had ADHD, you may benefit from reading these suggestions, because coming out tends to be an ongoing process.

Before we begin

Several viewers of my ADHD YouTube channel had asked for advice on coming out. When I started my response, I initially stumbled over whether one comes out “as ADHD” or “with ADHD”. I recalled a discussion ten years ago at an ADHD support group. At the time, as a psychiatrist and neuroscientist, I framed ADHD as a mental health condition that one had or didn’t have.

But several group members preferred to say they “were ADHD” rather than “had ADHD”. They saw it as an analogy to “being gay” rather than “having gay”. ADHD was simply part of their identity.

Clinicians still make an official ADHD diagnosis by determining whether an individual displays symptoms of impulsivity, hyperactivity and inattention to an extent that is unusual for their age and cultural background, and that leads to dysfunction or distress. But many researchers, clinicians, and members of the ADHD community view ADHD as a form of neurodivergence — their brains work somewhat differently, and it is primarily their executive functions — how the brain processes, organizes, and responds to information, that is different. This neurodivergent framework seems more accurate, has greater explanatory value, and is less stigmatizing than the symptom checklist definition of ADHD.

I’m aware that some individuals protest that ADHD, and virtually all of our other psychiatric labels are worthless or meaningless. If these labels don’t help you, fine, don’t use them. But thousands of studies indicate that ADHD, as currently described, defines a meaningful group of people, provides general predictions of long term outcomes, and guides targeted treatments that reduce symptoms, improve quality of life and prevent premature death.

Before coming out

Certainty. Before coming out make sure that you really have ADHD. The best way to do so is to have an assessment with a mental health professional who is familiar with the condition. Numerous on-line symptom surveys claim to identify who has ADHD, but since all of the symptoms are things everyone does some of the time, these questionnaires often fail to distinguish ADHD from other conditions or from normal behavior. At the very least, check with someone who knows you to see if their observations of your behavior align with your own perception.

For children coming out to their parents for the purpose of obtaining a formal ADHD evaluation, I suggest listing your patterns of behavior that seem to indicate that you have ADHD, and stating that you want a medical assessment to achieve greater clarity as to whether it really describes you.

Motives. Why do you want to come out? Presumably part of it is to help others understand your behaviors, and to help them understand you. Those are two different things, because although our behaviors are a reflection of who we are, they aren’t the complete story. Indeed, often coming out with ADHD is to guide others to reinterpret your behaviors in a new way. The more clearly you understand your motivation for coming out, the more likely you are to develop a plan that matches that desire.

Goals. Although motives and goals can be closely intertwined, your goal is what you are hoping to achieve. Often a goal for coming out involves some expectation that others will not only change how they see you, but how they interact with you in the future. While it is fine to have such goals, remember that you can influence, but not control what goes on inside the minds of others. You have more direct ability to shape your own thoughts, feelings, plans, and actions than to change others.

Who. Think of who you want to share your ADHD with. This is a reminder that coming out is not an all or nothing process. Often people come out first to those they expect to be most accepting. Many people come out to friends and family but, at least initially, not to bosses or co-workers.

Education. Accept that there is an element of unfairness to being different, which may include the burden of having to explain your neurodivergence to others and help them understand it. You have to become the teacher. Some of your “students” will already be well-informed, some will be teachable, and others may never care or be able to learn.

Prepare resources with accurate information about ADHD, to share with those you come out to. Depending on the audience, this can be written articles or videos. Keep them simple, and direct. Regardless of how articulate you are, new information usually takes some time to sink in. Your audience will probably want to rehash and review what you’ve told them. Having the information in a slightly different wording or voice can help reinforce the message you have delivered.

Remember that there’s a wealth of misinformation about ADHD on the internet. Your audience is likely to do their own search and may well come up with statements that are inaccurate and might undermine your coming out. In addition to some short, focused references, you may also want to suggest some more in-depth books or videos on ADHD, but don’t expect others to digest a big volume of information, particularly at the onset of their learning journey.

Individualize. I know I said this at the beginning, but it’s helpful to remind yourself that there’s no one correct way for coming out. Follow your own unique path. This is a quest, not a test. You’ll have chances to circle back and reinforce or clarify your message.

While Coming Out

Plan a time. Coming out in the midst of an argument or crisis is not ideal. You’re likely to be less able to explain yourself, the other person is less likely to be able to listen, and the entire exchange is more likely to sound like an excuse than an explanation.

When scheduling a time to talk, allow for several minutes for you to present your thoughts and feelings, as well as leaving time for questions and follow-up.

Simple. You’ve probably been thinking about ADHD longer than your audience has; if this is news to them, they probably won’t be able to process too much information at the first go around.

In particular, two ADHD tendencies might make it hard to keep it simple. Distractibility makes it easy for those with ADHD to go off track. This can be compounded by noting that either in the past or at this very moment, others aren’t following what you’re saying, which can lead to trying to backtrack, explicate, reiterate, repeat, fill-in, correct, emend or patch over what you feel you weren’t crystal clear about the first time. This, of course, tends to confuse the audience even further.

Jot down a few take-home bullet points, and try to stick with them.

Another ADHD tendency, of hyperfocusing, or going down a rabbit hole, can also contribute to providing too much information. One of my patients calls these his “dawn of time explanations”. You don’t need to include everything, particularly during an initial discussion. Just highlight a few ADHD-driven behavioral patterns that are pertinent to your interactions with this person.You don’t have to explain everything about ADHD, fascinating as it may be.

Framework As I discussed above, describing ADHD as a form of neurodiversity which affects executive functions can be a useful and powerful framework. Of course those terms themselves, depending on your audience, may need explaining.

One way to describe neurodiversity or neurodivergence is that some brains are wired differently. These differences from “typical” humans might include the size of certain brain structures, the amounts of certain neurochemicals at specific locations in the brain, or the ways brain cells use energy.

Executive functions describe how brains process, prioritize and make use of information, which can encompass directing attention, sustaining concentration, working memory, planning, initiating and completing tasks, time awareness and management, impulse control, and emotional regulation.

It can also help to mention that ADHD is characterized by fluctuations in symptoms, that part of ADHD is being consistently inconsistent, and that often for those with ADHD, actions are driven by what is interesting more than by what is important.

Personalize Pick a few ADHD-driven patterns of behavior that have led to problems for you, and phrase them as “I do these things (ramble on with my answers, stare out the window, get off track before completing my homework), which are tied to this ADHD symptom (distractibility).” because Y” Making I-statements makes your coming out personal, puts you in the position of taking responsibility. Providing examples makes ADHD concrete for your audience.

Patterns not events. You’re in a stronger position if you describe patterns rather than specific events. Saying “I’m often late for (appointments, lunches, turning in homework) because part of my ADHD is trouble with time management.” helps others to see how seemingly disconnected behaviors are actually related to an underlying cause. A specific example can also be picked apart, not least because for any specific instance other factors in addition to your ADHD contributed.

Explanation not excuse. Present your ADHD as an explanation rather than an excuse. People don’t like to hear excuses. When you clarify that your ADHD contributes to a pattern of behavior, it can actually lead to more effective measures to change these behaviors. Understanding that a behavior wasn’t simply due to “laziness”, or “willfulness”, or “resistance” or “denial” but instead flowed from your ADHD can help identify effective remedies. (Having a whiteboard near my desk helps remind me of what my tasks for today are. When you hear me going off target in conversation, it’s helpful to redirect me.)

After coming out

Resources. Make sure your audience has in hand a hardcopy or a link to a useful summary about ADHD. Two of my articles about what ADHD is and what ADHD is not may be helpful here, but CHADD, the nationwide patient and family support group for ADHD, ADDitude magazine, and the video channel How to ADHD are also good places to start.

Ongoing. Educating others about ADHD is a process, not a one and done. Almost certainly there will be aspects of ADHD, or nuances regarding your condition that you didn’t have time to describe. Don’t feel bad about not including everything; this is a quest not a test. Remember, you’ve started an important ongoing dialogue, it doesn’t matter how much you crammed into the first session.

Time. Give the other person time to reflect, come up with questions, think about what you’ve told them. People learn and process at their own rates.

Self care. Sharing something important about yourself, particularly something that differentiates you from many others, and that may have led to criticism or stigmatization in the past, is a big step. Congratulate yourself. Give yourself a reward, or at least take a break from other arduous tasks until you feel ready for them again.

Community. If you have a therapist, make use of them. In addition, friends with ADHD, or online communities can help you unpack and deal with any elation, disappointment, resentment or other feelings that might have come up from your coming out as ADHD. You’re not alone.

Certain audiences deserve special attention

Family. Coming out to family members is likely to be emotionally laden, particularly since rejection by family can feel devastating. Some families resist hearing about ADHD.

ADHD has a strong genetic component, meaning that there is a high likelihood that ADHD or strong ADHD traits run in your family member. Sometimes this can make the coming out a bonding and connecting experience. But ADHD in family members can also contribute to resistance and rejection for a number of reasons:

• obliviousness

• normalization

• individual differences

• denial

• jealousy

ADHD affects directing and sustaining attention. It’s really possible that family members with ADHD didn’t even notice your tardiness, or failing to turn in homework, or other behaviors that seem glaringly obvious to you, because they weren’t paying attention.

Even if they were aware of your ADHD-driven behaviors, they might resemble their own habits so closely that they just considered such actions to be normal. They may have minimized that there could be any negative consequences to such behavior, or dismissed this as just what one would expect to happen. Or their ADHD may manifest so differently from yours that they have trouble realizing underlying similarities.

Some people, particularly those from previous generations, spent large chunks of their life without awareness of their own ADHD. Coming out about your own ADHD may force them to confront their own ADHD. They may not be ready to look at their own ADHD, and through their own fears or other negative feelings may not be available to help with your journey of addressing your ADHD.

In particular, people whose own early years were scarred by fallout from their ADHD may — even if they love you — be jealous that you’ve figured out this challenge at an earlier point in life, or may resent that there are more resources and understanding for those with ADHD than they had available at a similar age.

ADHD is also over-represented among those who were adopted. This stems from an increased tendency that those with ADHD are more likely to become parents without being ready for it and thus put infants up for adoption, and because of possible mismatches between infants and their adoptive families. Among those who were adopted, especially those who were told that their adoptioin meant that they were specifically “chosen” or “selected,” coming out as ADHD may be particularly difficult due to fears of disappointing adoptive parents, or being viewed as being as a problem, or being defective.

School. It surprises me in this day and age, but I’ve seen numerous well meaning, otherwise capable teachers, from elementary through college level, who don’t seem to grasp that intelligence is a separate domain from ADHD — that there is a difference between what you know versus how you learn and express what you’ve learned.

Work. In the US, at the federal level as well as in most states, ADHD is recognized as a potentially disabling condition, and as such requires employers to make reasonable accommodations to help with performance. You’re usually in a stronger legal and ethical position if you have brought up your ADHD before it contributes to any impairment in your performance.

Accommodations. I think that we should be framing accommodations as efficiencies. These aren’t special perks granted to you that require a sacrifice from your teacher, manager, or workplace. These are efficiencies that are being made so that you can work more productively, and contribute to the team’s goals.

Strength Through Diversity

We’re living through a particularly strange time, when some powerful individuals feel threatened by, and deride, diversity and inclusivity. Yet the very basis of natural selection and human evolution is based on there being underlying genetic diversity, because different traits convey adaptive value in different circumstances. Some of our most compelling stories, from The Wizard of Oz to Harry Potter, highlight that having a broad range of capabilities makes groups of humans more resilient and capable. Yet we have bureaucrats who think that all soldiers need to have testosterone levels within a narrow range, or that women and other minoritized individuals can’t be effective leaders.

It’s not just that the pendulum will swing back at some point. The ignorance and spitefulness displayed by those currently overvaluing conformity consigns such views to failure. To deny or denigrate human differences makes little sense.

The communities that are strongest find ways to collaborate with even their most diverse members.

Coming out as ADHD is a step towards owning your own life, and contributing more fully to society.

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