Long Term Use of ADHD Medication and Cardiovascular Outcomes

 

 

I have several posts on this blog about prescribing ADHD medications with a goal of minimizing adverse psychiatric and medical side effects.  Like all medical treatments, close follow-up and monitoring is required to assure efficacy while reducing the risk of adverse effects.  To a trained physician it does not take much effort other than being rigorous in examinations and discussions with patients. In the area of ADHD, there is the frequent assumption that patients are young, healthy, and can probably tolerate medications better than older populations. With the increasing diagnosis of adult ADHD, all the comorbidities need to be carefully addressed and a recommendation of no treatment also needs to be considered.

Who have I advised against treatment? Older adults with obvious cardiovascular problems that are inadequately treated or controlled who may or may not have ADHD.  I do not really care if you are 60 years old and I think you really have ADHD, I am not going to start treatment if your blood pressure is not in good control or if you have other unstable conditions like angina, congestive heart failure, cardiomyopathy, or arrhythmias.

The commonest reason for not treating people was hypertension, measured by me in the office.  In some cases, there was an abnormal ECG showing a previously unknown arrhythmia. It can be difficult to tell a patient that you will not treat them because of a medical condition – but that is just the way it is.  Even if treatment is started – blood pressure monitoring needs to occur at every visit.  In some cases, I recommend that the patient purchase a home blood pressure monitor and send me the results.  Referring the patient to their primary care physician or cardiologist is useful to let that physician know that their patient wants stimulant treatment and provide feedback on what your assessment of their cardiac status was.  It is common for physicians prescribing adequate does of antihypertensives to not know that their patient is still hypertensive. It is always clear that the decision to prescribe stimulants is made by me and does not depend on the opinion of another physician.

White coat hypertension (WCH) is not an exception.  WCH is the idea that people get hypertensive related to the stress of being in physician’s office.  Conventional wisdom was that resolved when the patient left the office and therefore this was a being condition. The problem with that assessment is that it depends on knowing that the blood pressure did normalize away from the office.  That lead to a more modern definition that required ambulatory blood pressure measurements away from the office and subsequent more detailed definitions. As an example, the European Society of Hypertension recommends the following:  subjects with office systolic/diastolic blood pressure readings of ≥140/90 mm Hg and a 24-hour blood pressure <130/80 mm Hg.

In the most recent review, the authors do an excellent job pointing out some of the flaws in the early research that led to no significant differences between subjects with WCH and controls.  The control subjects often had cardiovascular disease or were treated with antihypertensives.  They also make the distinction between white coat effect (WCE) and white coat hypertension (WCH). WCE is defined as “an alerting reaction working through reflex activation of the sympathetic nervous system.”  A standard research technique to assess stress effects on blood pressure is to ask subjects to do mental arithmetic and it generally leads to a blood pressure effect like what the authors describe in this paper of 20 mm systolic or 10 mm diastolic.  The authors provide guidance on differentiating the various combinations of white coat hypertension and hypertension as well as providing guidance for future research.  In the office for the purpose of prescribing stimulants the key question is whether there is a white coat effect, white coat hypertension, and whether it occurs in the context of treated or untreated hypertension. Short of ambulatory blood pressure measurements other sources can provide some additional guidance.  Access to the electronic health record can show long term trends.  If indicated - I would not hesitate to suggest that the patient consult with their primary care physicians or hypertension specialist for ambulatory BP measurement.         

Studies have shown that patients who continue to exhibit a reactive blood pressure problem at home have similar cardiovascular risks to hypertensive individuals.  On the flip side, I have assessed many distressed patients in inpatient settings who were normotensive.  Based on this experience, I do not dismiss elevated blood pressure readings in the office especially if I am going to prescribe a medication that may elevate blood pressure.  

That brings me to the paper that led me to write this post (1).  This is a nested case control study of registry data in Sweden that looked at 10,388 cases of ADHD and 51,672 matched controls (aged 6-64 years old).  Exclusion criteria included pre-existing cardiovascular disease, previous use of ADHD medication, and emigration or death before baseline (defined as day of first ADHD medication or diagnosis – whichever came first).  This study design basically looks at the defined illness (in this case ADHD) and then matches the selected cases to controls from the same cohort – in this case up to 5 controls without known cardiovascular disease.  The exposure in this case was ADHD medications including study period, including methylphenidate, amphetamine] dexamphetamine lisdexamfetamine, atomoxetine, and guanfacine.  The last two medications are nonstimulants and guanfacine has also been used as an antihypertensive medication.  The cardiovascular outcomes included: Ischemic heart disease, cerebrovascular disease, hypertension, heart failure, arrhythmias, thromboembolic disease, and arterial disease.  The statistics of interest were adjusted odds rations comparing cases to controls.  The authors also did a brief literature review in both the introduction and discussion sections of the existing literature in this area and what can be described as mixed results.

Their main finding was that only two cardiovascular conditions – arterial disease and hypertension were significantly associated with stimulant medication use but not with atomoxetine or lisdexamfetamine use.  Risk also increased at a level of 1.5 DDD (defined daily doses) of stimulant medication.  Those specific doses except for guanfacine can be found at this link. 

The authors do a good job of interpreting the limitations of their data including the possibilities of under detection of the true rate of cardiovascular disease at baseline, the possibility of mediation nonadherence and underestimating the effects of medication exposure, and confounding by severity could be an issue through the effect for more severe ADHD on lifestyle factors important in the genesis of cardiovascular disease (CVD). Finally, since the study eliminated subjects with existing CVD – stimulant exposure was not measured at all in that population. The authors advise very cautious treatment and monitoring of those individuals.

All things considered, this was a good approach to studying the effects of ADHD medication exposure and the development of cardiovascular disease on a significant sample.  It was a convenience sample from a pre-existing registry.  The authors point out that some treatment groups were very small and advocated for a similar study with a larger N.   Just looking at the trends in their tables, there is clearly significant cardiovascular disease in both the test and control subjects.  The odds ratios for medication exposure were low when they were significant.  Few medical variables were controlled for (obesity, Type 2 diabetes mellitus, dyslipidemia, and sleep disorders) and of those 3 out of 4 are more common in patient with ADHD (3).  More subtle forms of effects from ADHD like whether there are affective changes (typically irritability and anger) leading to hypertension or a white coat effect are unknown currently.

That leads me back to the need for close monitoring for cardiovascular risk factors and conditions before any medication is considered. The group with pre-existing cardiovascular disease is at highest risk and they have not been studied. My speculation is that even using a large health plan database those numbers (patients with cardiovascular disease started on ADHD medication) will be small.  Any real world clinical scenario where this is being considered should be approached as cautiously as possible and monitored the same way.   

 

George Dawson, MD, DFAPA

Photo Credit:  Sgt. 1st Class Shane Klestinski, Public domain, via Wikimedia Commons.  For full details click on the photo to see Wikimedia Commons page.  I chose this photo because several adults that I diagnosed with ADHD told me that they had adapted to work in warehouse management and logistics - in many cases that involved driving fork lifts. 

References:

  1:  Zhang L, Li L, Andell P, Garcia-Argibay M, Quinn PD, D'Onofrio BM, Brikell I, Kuja-Halkola R, Lichtenstein P, Johnell K, Larsson H, Chang Z. Attention-Deficit/Hyperactivity Disorder Medications and Long-Term Risk of Cardiovascular Diseases. JAMA Psychiatry. 2024 Feb 1;81(2):178-187. doi: 10.1001/jamapsychiatry.2023.4294. PMID: 37991787; PMCID: PMC10851097.

2:  Franklin SS, Thijs L, Hansen TW, O'Brien E, Staessen JA. White-coat hypertension: new insights from recent studies. Hypertension. 2013 Dec;62(6):982-7. doi: 10.1161/HYPERTENSIONAHA.113.01275. Epub 2013 Sep 16. PMID: 24041952.

3:  Chen Q, Hartman CA, Haavik J, Harro J, Klungsøyr K, Hegvik TA, Wanders R, Ottosen C, Dalsgaard S, Faraone SV, Larsson H. Common psychiatric and metabolic comorbidity of adult attention-deficit/hyperactivity disorder: A population-based cross-sectional study. PLoS One. 2018 Sep 26;13(9):e0204516. doi: 10.1371/journal.pone.0204516. PMID: 30256837; PMCID: PMC6157884.

4:  Fuemmeler BF, Østbye T, Yang C, McClernon FJ, Kollins SH. Association between attention-deficit/hyperactivity disorder symptoms and obesity and hypertension in early adulthood: a population-based study. Int J Obes (Lond). 2011 Jun;35(6):852-62. doi: 10.1038/ijo.2010.214. Epub 2010 Oct 26. PMID: 20975727; PMCID: PMC3391591.

ADHD - 28 Discussion Points

 

There was some of the usual controversy in the media today.  Is Attention Deficit~Hyperactivity Disorder over diagnosed or underdiagnosed?  The usual controversy contained the usual stories of how easy it is to get a diagnosis of ADHD in some places.  In some places it seems like just a matter of expense - a thousand dollar test battery. In other places there are people disabled by the condition who cannot get adequate treatment.  In the meantime there are international experts cranking out reams of papers on the importance of diagnosing and treating this condition in childhood. Occasionally an article shows up in the papiers about the cardiovascular safety of these medications. And in the New England Journal of Medicine there was a paper about a higher incidence of psychosis due to these medications.  Where does the reality lie?

I was fortunate enough to have worked at a substance use treatment center for about 12 years just prior to retiring. Only adults were treated at that facility. A significant number of them were diagnosed and treated as children. There were also a significant number of patients newly diagnosed as adults - some as old adults in their 60s and 70s. Whether or not ADHD can occur as a new diagnosis during adulthood is controversial and establishing a history consistent with childhood ADHD is problematic due to recall errors and biases. Secondary causes of ADHD in adults such as substance use problems and brain injuries increases in prevalence.  Although I am speculating, secondary causes seem a more likely cause of attentional symptoms in adults and therefore acquired ADHD without childhood ADHD if it does exist is an entirely different problem.

Prescribing stimulants to patients who may have stimulant use disorders is problematic for a number of reasons. Initially we had an administrative safeguard on the practice. Stimulant prescriptions could only be approved with a second opinion by another psychiatrist after reviewing the record. Eventually we had a core of psychiatrists who practiced the same way and the second opinion was no longer necessary.  Over the course of 12 years I developed these discussion points.  I think they are a good example of the minimum ground you need to cover in an evaluation for ADHD.  I typically had a 60-90 minute time frame to work with and could see people on a weekly basis for 30 minute follow ups. These evaluations were often controversial and resulted in collateral contacts, typically with a family member who was advocating for the stimulant prescription. 

A few basic points about ADHD and establishing the diagnosis. Like many psychiatric disorders there is no gold standard test.  Like some of the media discussions, I have been told that a person underwent days of testing before they were given the diagnosis of ADHD.  These are typical paper and pencil tests, but there have also been tests based on watching a computer screen and even crude EEG recordings. There are a few places that use very sophisticated brain imaging techniques. Unfortunately none of these methods can predict a clear diagnosis or safe and effective use of a medication that can reinforce its own use.  That leaves clinicians with diagnostic criteria and and a cut off based on functional status as a result of those symptoms.  That may not sound like much, but it eliminates a large pool of prospective ADHD patients who have no degree of impairment and those who are obviously interested in possible performance enhancement rather than ADHD treatment.  

Stimulant medications are highly abusable, as evidenced by several epidemics of use dating as far back as 1929. We are in the midst of a current epidemic.  For those reasons it is important not to add to the problem as either the individual or population levels. In my particular case, I was seeing patients who were all carefully screening for substance use and adequate toxicological screening. Since they voluntarily admitted themselves into a treatment center it was also more likely that they recognized the severity of the problem and were more open to treatment.  Even against that background - it is worth covering the above points.  Covering those points often involves repetition because of cognitive problems in detox or disagreement.

These are just a few health and safety considerations. My main concern in this area is that psychiatric treatments somehow have the reputation that they don't require medical attention. They are somehow isolated from the rest of the body. The person prescribing this medication needs to assess the total health status of the individual and determine if the medication prescribed is safe to use. Cardiac and neurological conditions are at the top of that list. I gave a blood pressure example because I have been impressed with how many people tell me that their blood pressure was not checked after a stimulant prescription or a stimulant was started despite diagnoses of uncontrolled hypertension, cardiovascular disease, cardiac arrhythmias or cerebrovascular disease.  These were typically new prescriptions in older adults with no prior history of ADHD.  

Coexisting psychiatric disorders are also problematic. Most have associated cognitive symptoms if they are inadequately treated. That is not a reason to diagnose ADHD or start a stimulant medication.  Typical symptoms that can be caused by stimulants are have to be recognized and the medication must be stopped if adjusting the dose is not helpful.

It is important to keep the range of biological heterogeneity in mind. Once you have narrowed down a population of people who most likely have ADHD, they will not all have a uniform response to medication.  They may not all want to take medication.  As adults many stopped taking ADHD medication and adapted to a work and lifestyle that works very well for them. That is a very suitable outcome for an initial assessment.  There is another group who want to try a verbal therapy for ADHD in some cases because they recognize they can no longer take stimulants because they were escalating the dose. That is also a suitable outcome for the assessment. In those people who have ADHD are want to take a medication, I think a non-stimulant medication like atomoxetine is a good place to start. In my experience it works very well.  Disagreement about stimulants, especially in people with a stimulant use disorder typically requires extended conversations with the patient and their family. A quality control initiative can provide very useful data for that conversation. I suggest that any clinic or clinician who prescribes stimulants collect outcome data on those prescriptions.  The key piece of data is a comparison of the relapse rate of those patients taking stimulants compared with patients treated with non-stimulants. Other data could be collected as well - like how long the prescriptions were refilled. There are rules about collecting that data depending on your practice setting.  Check those rules first.  Outcome data will be the best data on whether a correct decision was made about prescribing the stimulant.

I added the following slide based on polypharmacy considerations in the paper cited in reference 1.  This is a common clinical problem that needs to be approached rationally and that includes limit setting on the concept that every side effect or symptom needs to be addressed by a medication rather than a medication discontinuation, reduction, or substitution.  I always include a discussion of rare but serious side effects, synergistic side effects, drug interactions, interactions with comorbid medical problems and associated medications, and very serious interactions that could lead to hospitalization or death, like serotonin syndrome. 

I am going to end on a note about countertransference based on a disagreement I had at a conference about my methods. The speaker advocated for prescribing stimulants as a general operating practice for anyone with ADHD. When I confronted him about the problem of substance use he claimed his motivation was that he considered it his priority to "help" people and he thought that stimulants were the most helpful medication.

Whether or not a medication is helpful for any psychiatric disorder depends on a very careful assessment and clinical expertise that considers several dimensions including the potential risks and benefits for the patient and the incorporation of the patient preferences and values into the clinical decision making process.  In my evaluations, I try to sum all of that up in an informed consent discussion. In the area of ADHD evaluation and treatment, that covers a lot of ground and there is no simple uniform recommendation.

George Dawson, MD, DFAPA

Photo Credit:  Many thanks to my colleague Eduardo A. Colon, MD for allowing me to use his photos. 

Take Your Meds

"It might be because I have severe ADHD.  It might be because it was jet fuel.  I don't try to draw the line".  - Stimulant user rationalizing use.


The above comment was made by a young man in the new Netflix documentary "Take Your Meds" about stimulant medications (but mostly Adderall).  Fortunately or unfortunately depending on your viewpoint - physicians are still charged with the task of drawing the line.  I don't typically like watching documentaries, but since this is my area of expertise I thought I would watch this one.

From the outset, it was apparent that the real downsides of using tremendously addictive drugs were not going to be emphasized.  This was a sanitized version of abusable drugs.  It was stated that prescription stimulant users were a class apart from methamphetamine users.  There seemed to be an implicit message that in an egalitarian society - if the methamphetamine users had access to stimulants they would be better off. If we all could get access to performance enhancing drugs like stimulants the world would be a better place.  A neuroscientist known for this kind of social commentary made some remarks basically stating that prescription stimulant use is another example of class factors in addiction.  In this case because over half of the story was performance enhancement - that class argument was also made.  Are those lower socioeconomic kids losing out because they don't have access to this performance enhancement?  Probably not because the film makers don't present any data that performance enhancement actually occurs.  It is the idea of performance enhancement. 

A modicum of of common sense and medical use was introduced.  They showed a very concerned pediatrician treating children of mothers who had some expertise in the field and nothing seemed to help their sons than stimulant medications.  In one scene the pediatrician spends a time convincing one of these teenagers that it is up to him to take the medications. I do not know how doctors can have those conversations in awkward examination rooms with the unexamined identified patient sitting on an exam table and the doctor just standing there talking.

We meet a number of individuals over the course of the documentary.  The first is a new college freshman.  She is the first to comment the competitiveness/ performance enhancing aspect of stimulants - namely "Everybody here is on them.  They are traded and sold.  In order to be competitive I have to be on them."

We meet a former professional football player who starts taking them.  We learn about how great he felt and how much of an advantage it seemed to make in all aspects of his play and in overcoming injuries.  We learn that in the NFL, if you are a player you can get an exception to play with stimulants and take them if a doctor says that you have ADHD and then only the prescription written by the doctor.  In this case the prescription was for Vyvanse 70 mg per day with 2-10 mg Adderall as needed on top of the Vyvanse.  The Adderall was occasionally increased to 20 mg twice a day in addition to the Vyvanse.  Either way he is taking more than the recommended total amount of stiumlant per day.  One day before the game, the player in this case ran out of his usual stimulants and took Concerta (methylphenidate) from another player.  Concerta had a different profile on toxicology screening and as a result he incurred a 4 game suspension.  The details of what happens next are not clear but we see him when he is not longer playing professional football and has moved on with his life.  In an interesting postscript, he talks about the conflict of being a different person on stimulants and what it means to take credit for what that person does.

We meet a Wall Street researcher and coder.  We get opinions on what coders think of using stimulants to write code and their aspirations to write perfect code.  He paints a picture of what it is like to work for a large investment concern.  A room full of people on computers, expected to work very long hours and get rapid results.  If additional time is needed, the plan is to take stimulants and get the work done.  One night he declines stimulants, leaves work and the guy next to him stays there and at some point has a seizure from stimulants.

The common threads are the idea that stimulants are used as performance enhancers to be more competitive in academic and business environments. The idea is that every student and worker is expendable and if they can't do the job, somebody else will step up and do it therefore stimulants are necessary.  Some seem annoyed by the charade of having to convince a doctor that they have ADHD in order to get a stimulant prescription.  They would prefer just to get it without any medical diagnosis.  Hallucinogens are brought up as additional performance enhancing agents - especially microdose hallucinogens.

There are the usual suggestions that this is a pharmaceutical marketing phenomenon.  There is a brief discussion of America's first amphetamine epidemic and how the Controlled Substances Act was used to shut it down.  The producers do mention that adult prescriptions for stimulant medications now exceed the prescriptions for children. They touch on problems with a totally subjective (first-person report) and a lack of clear objective markers for a diagnosis - but not the amount of fraud that goes on to get these prescriptions.  Nobody ever points out for example, that none of these otherwise high functioning adults would qualify for the diagnosis on level of disability alone.                 

The only small bit of scientific data in the film was the work done by Farah, et al (1) who looked at the performance enhancing properties of amphetamines in health college students.  Across a large number of neuropsychological variables it seems that the only one that was significantly improved was the persons perception of their performance.  In other words, there was no objective sign that their performance was enhanced on cognitive testing but the subjects all believed they were performing better. There is more data that the performance enhancing aspects of stimulants are overblown.

That is certainly my experience interacting with amphetamine users for the last 30 plus years.  I caught the tail end of the first epidemic and starting seeing obese patients on high dose amphetamines.  Even though they had not lost a pound and were still very obese, they insisted on staying on high dose stimulants and were fearful they would gain weight if they stopped.  In those days it was not uncommon to get a call to the Emergency Department because there was a narcoleptic patient there form another state who was taking high dose stimulants (> 100 mg/ day of amphetamines) for narcolepsy.  My job was to figure out if the patient really had narcolepsy or they were lying to get stimulants.

Today my job is a little more subtle.  Adults are operating from many levels of misconception about both stimulants and ADHD.  Today I rarely meet an adult who does not think they have ADHD - even if they have a superior level of academic and vocational achievement. In some cases they have been swayed by the non-specific effects of stimulants - "I took my son's Adderall and for the first time I was able to focus and read well."  In many cases they are influenced by professionals who have heard about the high heritability of ADHD and interpret this to mean if they diagnose a child with ADHD it means the parents and in some cases the grandparents have it.  I have seen generations diagnosed this way.  I  work in the addiction field and everyone who is addicted to stimulants believes that they cannot live without them. They get quite angry if they are not supplied.  That same population is in withdrawal form using very high doses of prescription or non-prescription stimulants and they also present with a residual ADHD that cannot be distinguished from ADHD but it is due to acute and chronic changes from stimulant overuse.  Last but not last, the medical and potential medical complications of amphetamine use need to be carefully determined.  Hypertension, cardiac changes,  arrhythmias, and movement disorders are all fairly common in people who overuse stimulants.

 These are a few of the major points that the Netflix documentary leaves out.  It touches a few of the high points but like most media pieces it gets too focused on human interest stories.  Historical lessons like what happened during the First Amphetamine Epidemic seem to be lost.  When that ended in the 1970s even the rock bands of that era were sending the message that "Speed kills!"  Addiction is more likely to happen if it is taken because for performance enhancement.  Any time a person operates from the perspective that taking a medication will greatly enhance their performance, it is difficult to not think that "more is better."

If you are a bottom line person, I think you will be disappointed if you want to learn some science about ADHD and stimulant treatment in this documentary.  You will hear a few sound bites but not much more.  If your interest is more in the pharmaceutical industry selling stimulants and marketing them excessively, you will also get the superficial story.  There is much more detail on annual prescriptions and trends.  On a historical basis, I produced a timeline extracted from a history of America's first amphetamine epidemic that covers everything in the film and more without the film clips of Jack Kerouac.  If you are an addiction specialist like I am, I think there is a message there that most of the prescriptions for adults are not for ADHD but for some type of cognitive enhancement and the basis for that is thin.  That is a good take away message, but the real downside is not that apparent.

That downside is addiction.  Compulsively using stimulants to the point that your life, your relationships, and your health are destroyed is as possible with prescription stimulants as it is with methamphetamine.  Both are sold on the street by the same dealers.  Contrary to what you read in the press or pick up in this film all it takes is exposure to amphetamines and the right genetic make-up to create an addiction.  Having true ADHD, or the right socioeconomic standing, or willpower doesn't protect you against addiction.  Once an addiction to prescription or nonprescription stimulants occurs it is a very difficult problem to recover from.  Unlike opioids and alcohol - there are no known medications to assist in recovery. 

So like most treatments in medicine, stimulants need to be cautiously applied.  Indiscriminate use for performance enhancement does not seem like a good idea to me because it will cause proportionally more addiction and the cognitive gains across the population are minimal mostly restricted to the  perception that you are doing much better than you are. 

Not a good reason for taking stimulant medications unless you really need them.


George Dawson, MD, DFAPA
 





References:

1: Ilieva I, Boland J, Farah MJ. Objective and subjective cognitive enhancing effects of mixed amphetamine salts in healthy people. Neuropharmacology. 2013 Jan;64:496-505. doi: 10.1016/j.neuropharm.2012.07.021. Epub 2012 Aug 1. PubMed PMID: 22884611.

2: Smith ME, Farah MJ. Are prescription stimulants "smart pills"? The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals. Psychol Bull. 2011 Sep;137(5):717-41. doi: 10.1037/a0023825. Review. PubMed PMID: 21859174

3: Bagot KS, Kaminer Y. Efficacy of stimulants for cognitive enhancement in non-attention deficit hyperactivity disorder youth: a systematic review. Addiction. 2014 Apr;109(4):547-57. Review. PubMed PMID: 24749160.

Addiction and ADHD - The Bullet Points

Figure 1.  from Shaw M, Hodgkins P, Caci H, et al. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment.  BMC Med. 2012 Sep 4 10:99 (see ref 6 below).

One of the main concerns in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) is whether treatment improves outcomes.  The outcomes measure of interest may depend on the clinical population that you are focused on treating.   In primary care settings, my impression is that a lot of the adults treated by internists are relatively stable and that they do not have a lot of problems with other mental illnesses or addictions.  That is my speculation based on some of the numbers of adults I have heard are seeing primary care physicians and the fact that seeing those numbers with even a fraction of patients who have additional psychiatric problems or addictions would be unsustainable.  I have also directly observed the pattern that many patients who are discharged from primary care for stimulant overuse or psychiatric complications like mania end up seeing psychiatrists.  As a psychiatrist working in a residential setting that treats substance use problems - trends in overprescribing, misdiagnosis and confusion about the concept of addiction and ADHD treatment are readily observed.  It is very clear that people with clear ADHD can misuse stimulants and continue to insist on using stimulants.  It is clear than many of these people develop insight into this and can say at one point that they can no longer take stimulants even though they have a bona fide ADHD diagnosis.  It is also clear that there is a lot of confusion among treating professionals about the issue of whether or not a stimulant should be prescribed to a person with an addiction.  

There is a lot of overlap between the diagnosis and treatment of Attention-Deficit/Hyperactivity Disorder and addiction or substance use disorders.  Discovering this overlap depends on clinical experience, training and exposure to patients with addictions.  It is fairly common to read studies about ADHD outcomes that may not look at addictions as outcomes.  Like many areas in medicine, some of the early studies in this area have not been borne out by subsequent studies.  The study of this problem has only been a relatively recent endeavor.   The original AHRQ report in 1999 (1) looked at 77 randomized controlled clinical trials included in the time period from 1971 to 1999.  Half of the studies were published since 1990.  At that time there were only 13 adult studies.  The outcome variables were generally improvement on symptomatic rating scales, neuropsychological tests or educational achievement tests.    

Connor's review (2) looks at the studies prior to 2006.  At the time he states that there were a total of 14 studies that looked at potential abuse issues.  One of the studies supported the idea of behavioral sensitization or stimulant administration leading to craving and eventual self administration.   That study did not control for Conduct Disorder, a comorbid condition  that increase the risk of substance use disorders.  The other studies found no increased risk, and in some cases a decreased risk of substance use disorders.  There were no review elements that looked at addictions or substance use disorders.  A meta-analysis of 6 studies by Wilens, et al showed a 1.9 fold reduction in risk in the stimulant treated patients.  Connor's conclusion is that "...in uncontrolled environments, active substance abuse is a relative contraindication to prescribing stimulant medications."  the use of atomoxetine or antidepressants with a known efficacy for ADHD was encouraged (p. 626).

A more recent review by Shaw, et al from 2012 takes a different approach.  The authors looked at studies between 1980 and 2010 with a minimum follow-up period of two years or more (prospective or retrospective) or cross sectional studies that compared two ages differing by two years of more.  Nine separate outcome measures were examined as indicated in Figure 1 at the top of this page.  Since some studies reported more than one outcome measure, a total of 636 outcomes were examined from the 351 studies reviewed for this paper.  Drug use or addictive behavior was one of the most frequently examined outcomes with a total of 160 results.  The next most frequent result was academic functioning with 119 results.  The data is represented as percentage comparisons as improved, similar, or poorer than the comparators.  As an example in Figure 1, the last 4 categories show that treatment was beneficial in 67% of the drug/addictive, 50% of the antisocial, 50% of the service use outcomes, and 33% of the occupational outcomes.  The authors conclude that in these four treatment groups there was no benefit conferred by treatment.  They looked at the issue of treatment of these four groups in the rest of the world and found that there was substantially better outcomes for this subgroup.  There were significant methodological problems noted in the studies including the need to control for Conduct Disorder, Oppositional Defiant Disorder, and a number of other comorbid psychiatric disorders.  Other potential comparison issues between the American and non-American studies included the fact that the American studies were largely prospective, the non-American studies used more stringent ICD-10 codes.  One of the main variables that addiction psychiatrists are focused on clinically is when the addiction is established.  Did it occur before, during, of after the ADHD diagnosis in childhood?  What does that spectrum suggest for the impact of stimulant treatment on an addiction outcome?

Where does all of this leave clinicians today?  It is possible to find clinicians who believe that they are treating addiction with stimulants because they are reducing impulsivity associated with ADHD.  There are also clinicians who believe that stimulants must be avoided at all costs, even in people with a diagnosis of ADHD.  Is there a rational approach to discuss what is known about the diagnosis and treatment with the patient as part of their overall treatment program that might optimize treatment outcomes?  I think that there is and have written it down in this worksheet entitled 28 Discussion Points for Stimulant Treatment of ADHD.  The worksheet is intended to address problematic diagnosis as the first point of variance.  It discusses the relevant addiction and safety considerations.  There is also a framework for exploring the decision to use a stimulant in the broader context of a treatment plan that may include non-medical therapists and treatment programs and housing programs that may limit or prohibit the patient from using stimulants.  It does not incorporate the therapeutic alliance and overprescribing considerations.  One of the most difficult tasks for physicians is not prescribing a medication with addictive potential when a person believes it is necessary for their life or they are demanding it.

Remembering that people with addictions are compelled to take stimulants whether they improve outcomes or not is an important part of providing quality care to this population.
 

George Dawson, MD, DFAPA



References:

1:  Jadad AR, Boyle M, Cunningham C, et al.  Treatment of Attention-Deficit/Hyperactivity Disorder.  Evidence Report/Technology Assessment No. 11 (Prepared by McMaster University under Contract No. 290-97-0017).  AHRQ Publication No. 00-E005.  Rockville, MD:  Agency for Healthcare Research and Quality.  November 1999.

2:  Connor DF.  Stimulants.  In: Barkley DF.  Attention-Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment.  3rd ed.  New York, NY.  The Guilford Press, 2006: 608-647.

3:  Barkley RA, Fischer M, Smallish L, Fletcher K. Does the treatment of attention deficit/hyperactivity disorder with stimulants contribute to drug use/abuse? A 13-year prospective study. Pediatrics. 2003 Jan;111(1):97-109. PubMed PMID: 12509561.

4:  Wilens TE, Faraone SV, Biederman J, Gunawardene S.  Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics. 2003 Jan;111(1):179-85. PubMed PMID: 12509574.

5: Biederman J, Monuteaux MC, Spencer T, Wilens TE, Macpherson HA, Faraone SV. Stimulant therapy and risk for subsequent substance use disorders in male adults with ADHD: a naturalistic controlled 10-year follow-up study. Am J Psychiatry. 2008 May;165(5):597-603. doi: 10.1176/appi.ajp.2007.07091486. Epub 2008 Mar 3. PubMed PMID: 18316421.

6:  Shaw M, Hodgkins P, Caci H, Young S, Kahle J, Woods AG, Arnold LE. A systematic review and analysis of long-term outcomes in attention deficit hyperactivity disorder: effects of treatment and non-treatment. BMC Med. 2012 Sep 4;10:99. doi: 10.1186/1741-7015-10-99. Review. PubMed PMID: 22947230.  online at: http://www.biomedcentral.com/1741-7015/10/99


Attribution:

The graphic at the top of this post is from reference 6 above and is posted per the open access license at that site.

Robust Doses of Extended-Release Mixed Amphetamine Salts To Treat Cocaine Use Disorder

JAMA Psychiatry. 2015 Jun 1;72(6):593-602

This article (2) caught my eye in JAMA Psychiatry.  Stimulant (methamphetamine, cocaine, prescription stimulants, and various synthetics) use disorders (previously called addictions) are difficult problems to treat.  That is especially true because of the epidemic of adult Attention Deficit~Hyperactivity Disorder diagnoses and the cross contamination from the cognitive enhancement movement as well as new indications for stimulant prescriptions.   Stimulant medications are widely available and generally work at some level for most people who take them leading to the common impression that:  "I took my cousin's Adderall and it worked!  Therefore I must have ADHD and need my own Adderall prescription."  By the time that has happened it is usually very difficult for any physician to explain to this patient why a positive response to a stimulant does not equate to an ADHD diagnosis, especially if the prospective patient has been functioning at a high level and is presenting for diagnosis and treatment after doing extremely well in college and their first few years of professional school.

A second problem with the ADHD stimulant use issue is the misconception that people with "true" ADHD are less susceptible to the positive reinforcing effects of stimulants than people without ADHD.  There are certainly subgroups of person with this diagnosis that do not like to take stimulants.  They find that stimulants decrease their appetite, given them increased anxiety and insomnia, and in many cases leave them feeling more restricted, affectively blunted and less spontaneous.  I find that these patients are generally selected out by the time they are adults.  They had true ADHD diagnoses in middle school, did not like the stimulants, or in many cases their parents did not like the effect they were seeing and they were taken off of them.  They may have developed significant coping strategies based on their dislike of stimulant effects.  Like many adult psychiatric disorders there is no one uniform phenotype, and the phenotype of the person who was diagnosed either as a child or an adult and who gets a euphorigenic effect from stimulants and escalates the dose clearly exists and is seen in treatment centers.  In many cases they have an iatrogenic diagnosis of bipolar disorder from a pattern of taking the month's prescription of stimulant in the first one or two weeks and then either going into withdrawal or using a depressant like alcohol, benzodiazepines, or opioids to treat the dysphoria and cravings associated with stimulant withdrawal.

There is also the situation where a person has been using high dose prescribed stimulants (taking more than prescribed) or using high doses of meth or cocaine off the street, where they develop a residual state that is identical to ADHD, but where the cause of the ADHD is the stimulant.  I think it is an error to treat that residual state with stimulants.  That residual state is generally associated with a profound level of impairment and lack of insight.  The patient is aware of significant cognitive problems, attributes them to ADHD and often insists on treatment with stimulants despite a clear addiction to stimulants.  They may insist that years or decades of stimulant use was their attempt to self diagnose and treat their own ADHD.  It is very common for patients with substance abuse problems to give a history of no formal diagnosis in childhood, no school or occupational impairment, but to offer the opinion that they think they may have ADHD.  All of these considerations lead to associated problems in providing care to people who have clear ADHD and stimulant use diagnoses.  

That leads me to this multisite study (2) on the effects of high doses of extended release mixed amphetamine (ER MA) salts on both ADHD and cocaine use in patients who have both of these diagnoses.  The doses used were 60 and 80 mg/day.  The most commonly used current prescription versions of these drugs typically recommend a maximum dose in adults of 30 mg/day (1), but interestingly there is a "titrate to tolerability" statement in the package insert of a drug where 20 - 60 mg/day were used in trials with the statement  "There was not adequate evidence that doses greater than 20 mg/day conferred additional benefit."  The authors describe their dosing selections as "robust" and suggest that there is evidence that higher doses are needed to treat cocaine use problems.

Looking at authors methodology, their screening for this trial is instructive of the problems encountered in clinical practice.  Of a total of 1614 patients screened, only 126 were ultimately randomized to placebo, 60 mg/day ER MA, or 80 mg/day ER MA.  Five hundred and sixty two were screened out due to medical or psychiatric exclusion criteria.  It is common in older populations of stimulant users to find significant cardiovascular morbidity in the form of cardiomyopathy, coronary artery disease, and arrhythmias and these were some of the exclusion criteria.  The other aspect of this study that I really liked and would suggest implemented in everyday practice is the authors approach to blood pressure and heart rate specifically:

"Participants with blood pressure higher than 140/90 mm Hg or heart rate higher than 100 beats/min for 2 weeks or with single readings of blood pressure higher than 160/110mmHg or heart rate higher than 110 beats/min were discontinued from study medication." 

It is always shocking to hear from a person who has been on stimulants for years that nobody has ever checked their blood pressure or pulse, especially when they are sitting in front of you and are hypertensive and tachycardic.  This basic procedure should be done on any person taking stimulants, antipsychotics, antidepressant and for that matter any CNS active drug.  If similar effects are noted with any of these medications they should be discontinued.

Another important aspect of this study is that although the patients were well screened, they were complex from a substance use standpoint with current alcohol (18.6 - 27.9%), cannabis (7 - 14%), and nicotine (45-65.1%) use disorders.  The high levels of nicotine use are not surprising considering the epidemiological correlations between smoking and cocaine use and recent evidence about the epigenetic effects of nicotine in substance use disorders.  The authors do not comment on whether there were different outcomes for the non-smokers in this study.

On the primary outcome measure for ADHD - a 30% reduction in the AISRS (Adult ADHD Investigator Symptom Rating Scale) 58.1% of the high strength group and 75% of the low strength group achieved that outcomes with odds ratios of 2.27 and 5.23 respectively (see text for confidence intervals).  In terms of cocaine use outcomes the 80 mg dose resulted in fewer cocaine positive weeks (by any positive toxicology or report) and abstinence in the last three weeks.  The numbers are given in the table below:

High dose MA ER resulted in both a significant reduction in cocaine positive weeks over the 14 weeks of the study.  The 60 and 80 mg doses were actually fairly equivalent form a statistical standpoint and both were superior to placebo in terms of ADHD and cocaine outcomes.  But the real question is whether this is a reasonable clinical approach to this problem?  This was an intent-to-treat analysis with significant drop out rates.  The drop out rates are illustrated in the rapid decline in denominators in each group in Table 2.

In my experience, a substantial number of patients with ADHD and either cocaine or amphetamine use disorder reach the end of the prescribing algorithm where they have failed or relapsed.  In many cases that failure does not lead to a prescription being stopped for many reasons, a lack of information to the prescribing physician being foremost among them.  In the real world there is no clinic that will follow patients three times a week with toxicology screens at most of those visits and offer them all cognitive behavioral therapy.  Models currently funded by managed care companies and governments consist of patients being seen every one to three months for 20 or 30 minutes.  Many of those  visits are done by clinicians with little to no addiction experience.  Within the medication maintenance literature, particularly with buprenorphine maintenance there are studies that suggest psychotherapy adds nothing to the outcomes.  But even without that data what business manager would consider those therapists "cost effective" beyond the stimulant prescription?

A key element that I never see in these studies is the patient's subjective response to the stimulant at increasing doses.    I have found that Koob's definition of addiction is generally predictive:

"Addiction is a chronic relapsing syndrome that moves from an impulse control disorder involving positive reinforcement to a compulsive disorder involving negative reinforcement."

A euphorigenic, hypomanic effect is usually the high risk positive reinforcer regardless of the substance taken.  One of the theories of abuse deterrent approaches is that the pharmacokinetics of the substance used prevents rapid availability in the brain and this decreases abuse potential.  Many abuse deterrent preparations fail because multiples of the dose can be taken and result in the positive reinforcing aspects of the addiction cycle.  I consider the authors' paper to be elegant in its experimental approach.  The graphic at the top of this page is first-rate as a source of information.  It also illustrates the problem of coming up with a clinical trial that can be translated into practice.  I would not consider implementing this strategy as a clinical approach until there was a long term study that looked thoroughly at all of the outcomes.  At this time, I don't think the modest results of this short term study warrant the widespread practice of using extended release mixed amphetamine salts for cocaine use disorders.  There are also legal issues with prescribing maintenance doses of controlled substances in order to "maintain an addiction" as some laws are currently written.  I would have liked to see an attempt to characterize the subjective responses to methamphetamine use measured along with an analysis of whether the non-smokers did better than the smokers.

George Dawson, MD, DFAPA



References:

1:  Drug Facts and Comparisons.  Wolters Kluwer Health.  St. Louis, MO, 2013.

2: Levin FR, Mariani JJ, Specker S, Mooney M, Mahony A, Brooks DJ, Babb D, Bai Y,Eberly LE, Nunes EV, Grabowski J. Extended-Release Mixed Amphetamine Salts vs Placebo for Comorbid Adult Attention-Deficit/Hyperactivity Disorder and Cocaine Use Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2015 Jun 1;72(6):593-602. doi: 10.1001/jamapsychiatry.2015.41. PubMed PMID: 25887096; PubMed Central PMCID: PMC4456227

Attribution:

1.  The figure at the top of this post is from reference 2 above and is used with permission from the American Medical Association, License Number 3660331303348.  Copyright © 2015 American Medical Association.  All rights reserved.

How Do So Many People End Up on Stimulants?

There is no question that thousands if not millions of people end up taking stimulants unnecessarily these days.  Addiction psychiatrists,  have a unique perspective on this that I thinks goes beyond a typical approach to the problem.  I like to consider it to be grounded in behavioral pharmacology and neuroscience.   For the sake of this essay I will limit my remarks to all adults who are college aged or older and should not be taking stimulants.  Neuroscientific discoveries in the area of brain maturation suggest that a significant portion of the college-aged individuals might not make the same decisions they make a decade later, but the practical consideration is that there are millions of people in college making decisions about stimulants every day.  There are several ways to look at the problem.  The best approach I can think of is to look at the various ways that patients present for treatment.  The request for stimulant treatment can be subtle or overt.  Unlike some the papers in the current literature, I don't think that the diagnostic questions here are subtle.  During an initial clinical assessment - diagnosis and treatment commonly overlap and in some cases that I will illustrate treatment considerations become primary in the initial minutes of the interview.

The general psychiatric interview has always been a screen of sorts.  My recollection is that it was typically more problem focused in the past.  Over time, that interview started to incorporate more disorders as a focus of inquiry.  On the outpatient side the disorders added been primarily Post Traumatic Stress Disorder and Attention Deficit-Hyperactivity Disorder in non-geriatric populations.  Any time a screening is being done whether it uses a symptoms checklist or a lengthy interview there is always the chance of missing the true diagnosis or adding a diagnosis that is probably not there.  Here are a few examples.

1.  "I have been depressed for the past ten years...."  An inquiry about mood disorders at some point will focus on concentration.   Impaired concentration and attention span occurs in a number of psychiatric disorders.  Combined with some developmental history and a history of chronicity it is easy to see the problem as a missed diagnosis of ADHD and initiate treatment for that disorder in addition to the primary mood disorder.  There are problems with that approach especially when the history of the mood disorder is clear and it has never been adequately treated.

2.  "I have a diagnosis of bipolar disorder - manic and these medications aren't working...."  ADHD in adults rarely presents as hyperactivity so severe that it could be mistaken for mania.  Manic episodes are also phasic disturbances making it very unlikely that there would be many patients in any single practice who were both manic and had ADHD.  In the cases where it does happen stimulant treatment complicates the treatment of bipolar disorder and can lead to worsening mania, delusional thinking and hallucinations.

3.  "My son/daughter has ADHD....."  There are two variations in this interaction.  In the first, the parent is told about the high heritability of ADHD and advised that they also probably have it and can be assessed for it or mention to their primary care physician that they may need treatment for it.  In the second, the parent of a child with an ADHD diagnosis reads the diagnostic materials and comes into an appointment and says: "You know, I have read the symptoms and think that I have them.  Should I be treated for ADHD?"

4.  "I have always had a problem reading and I was  never any good in school..."  A common approach is to view this as ADHD, do the screening and proceed with treatment.  Physicians in general have had very little training in the assessment or treatment of learning disorder and although there is comorbid ADHD and learning disorders there is also a significant population of people with pure learning disorders who do not have ADHD.

5.  "I took my friend's Adderall and felt like I could concentrate and study for the first time in my life.  I did a lot better on that test...."  The population-wide bias is that stimulants are a specific treatment for ADHD rather than a drug that will temporarily improve anyone's energy level and attention span.  There is also the cultural phenomenon of cognitive enhancement or using stimulants as performance enhancing drugs that may be driving this request.  It is known that the availability of stimulants on campuses and in professional schools is widespread.  This is associated with students selling their prescriptions for profit and availability of stimulants illegally obtained for the purpose of cognitive enhancement.  The issue is further confused by position statements in scientific journals that support this practice.  I have not seen it studied, but it would be interesting to see questions and responses about cognitive enhancement asked at student health centers and practices that see a lot of college and professional students.

6.  "I have ADHD and need a prescription refill...."  It may be true that the patient has a clear-cut documented diagnosis prior to the age of 12 (DSM-5 criteria).  But what has happened since that initial diagnosis in childhood and now is critical history.  Has there been continuous treatment since then or has the treatment been disrupted.  Common causes of disruption include stimulant side effects, symptom resolution with age,  and co-occuring substance use problems.  A detailed history of the course of treatment since childhood is needed to make the decision to continue or reinitiate treatment.

7.  "I heard you had a test for ADHD...."  This question often initiates screening at a higher level.  There are any number of places with extended neuropsychological batteries, brain  imaging tests, or EEG tests that they claim will definitively diagnose ADHD.  In fact, there are no tests with that capability.  I have heard one of the top experts in the world on ADHD make that same statement and he was also a neuropsychologist.  I have had several years of experience with quantitative EEG machines and know their limitations.   At this point several hours of extended testing adds nothing to a detailed interview, review of collateral information, and symptom checklists to basically assure that all of the questions have been asked.

8.  "My meds need to be adjusted....."  This could be a question from a person in treatment for another problem or a person already being treated for ADHD.  The unstated issue here is the underlying belief that by adjusting a medication one's mental processes will be closer to perfection.  A child psychiatrist that I work with said it best:   "The goal in treating ADHD is to get them more functional, not to perfect their functioning."  I think the unrealistic goal of perfection drives a lot of prescriptions that exceed the recommended FDA limits.  It also explains a lot of "rescue medications" superimposed on sustained release preparations like Adderall.  Anyone familiar with the pharmacokinetics of sustained release drugs should realize why rescue medications (like immediate release Adderall on top of sustained release Adderall XR) are unnecessary.

9.  "I can't stay sober if I can't get treated for ADHD....."  This can be a complicated and confusing situation.  The child psychiatry literature had suggested initially that children with treated ADHD were less likely to have substance use disorders as adults than children with untreated ADHD.  As the evidence accumulates that is less clear.  Many adult psychiatrists and some addiction psychiatrists have extrapolated those equivocal findings to mean that treating a known or new diagnosis of ADHD in an adult will improve treatment outcomes for ADHD.  There is no evidence that is true.  Some addiction psychiatrists believe that the opposite is true, that there is a cross addiction phenomenon and that treating a person with an addiction makes it more difficult to stay sober from their drug of choice.  If the person is addicted to stimulant medication and has a clear history of accelerating the dose of stimulants or using them in unorthodox ways (intravenously, smoking, snorting, etc) it is very unlikely that person will be able to take a stimulant prescription in a controlled manner.  It is also very possible that the person making this request has a long history of experiencing prescription or street drugs as being necessary to regulate mental functioning.  That can be highly reinforcing even if the effects are sustained for hours or less.

10.  "I have been sober for one month and can't focus or remember anything......" Subjective cognitive problems are frequent during initial sobriety.  The substance used and total amount used over time probably determine the extent that the cognitive changes persist, but it is a difficult problem to study for those same reasons.  Clinicians know that there are cognitive effects but there is no standard approach to the problem.  From my experience, I think that two months sober is the absolute minimum time to consider evaluating subjective cognitive problems.  Even at that time getting collateral history about the person's cognitive and functional capacity and problem solving with them on work arounds would probably be the biggest part of the treatment.

The above scenarios are not exhaustive and I probably could come up with another 5 or 10 but they are illustrative of pathways to questionable stimulant use.  The common thread here is that anyone in these scenarios can endorse all of the symptoms of ADHD.  Figuring out what those symptoms are is fairly obvious on many checklists.  One of these checklists shows the symptoms and checkboxes necessary to make the diagnosis in grayed out panels.  It is easy to fake the symptoms in an interview or on a diagnostic checklist.  It takes a lot of hard work on the part of the physician to figure out not only who might be faking but also who has the symptoms but not the diagnosis.  One of the features of the DSM that was attacked by several critics during the pre-release hysteria was the "generic diagnostic criterion requiring distress or disability" to establish disorder thresholds (DSM-5 p 21).  In the case of ADHD that is Criterion D "There is clear evidence that the symptoms interfere with or reduce the quality of social, academic, or occupational functioning."  (DSM-5 p 60).

The diagnosis of ADHD is generally not the diagnosis of a severe functional disorder.  As a psychiatrist who practiced in a hospital setting most of the people I assessed clearly met the functional criteria by the time I saw them and diagnosed severe mood disorders, psychotic disorders, substance use disorders or dementias.   Many of them were by definition unable to function outside of a hospital setting.  It is an entirely different assessment when faced with a successful professional who has worked at a high degree of competence for 20 years who presents with any one of the above problems because they think they have ADHD.  It takes more than a review of the diagnostic criteria.   It takes an exploration of the patient's motivations for treatment.  What do they hope to accomplish by treatment?

It also takes a conservative prescribing bias on the part of the prescriber.  Stimulants are potent medications that can alter a person's state of consciousness.  They are potentially addicting medications and that can result in craving or wanting to take the medication irrespective of any therapeutic effect.  The wide availability of stimulants led to the first amphetamine epidemic in the United States.   When I first started out in psychiatry, I was still seeing people who became addicted to stimulants when they were widely prescribed for weight loss.   It is well known that the medications were ineffective for weight loss but people continued to take them at high doses in spite of the fact that they had not lost any weight.  In talking with people about what drives this many people feel like they are only competent when taking stimulants.   They believe that their cognitive and functional capacities are improved despite the fact that there is minimal evidence that this is occurring from their descriptions of what they are doing at work or in their family.

There are a number of strategies in clinical practice to avoid some of the problems with excessive stimulant prescriptions that I will address in a separate post.  My main point with this post was to look at some ways that people with mild subjective cognitive concerns, addictions, people seeking cognitive enhancement, people who have been functioning well but believe that they can function better come in to treatment for ADHD and get stimulant prescriptions.


George Dawson, MD, DFAPA

Supplementary 1:  Literature was used to construct these hypothetical scenarios.

Cognitive Enhancement IS Cheating

One of my colleagues posted a recent commentary from Nature on how the idea of the smart pill has been oversold.  The basic theme of the commentary is that there is no good evidence that treatment of ADHD with stimulants improves academic outcomes.  The author reviews a few long term studies and contends that differences between the medication and placebo seem to wash out over time and therefore there is no detectable difference.  Her overall conclusions seem inconsistent with her view that:  "For most people with ADHD, these medications — typically formulations of methylphenidate or amphetamine — quickly calm them down and increase their ability to concentrate. Although these behavioural changes make the drugs useful, a growing body of evidence suggests that the benefits mainly stop there..."

A question for any cognitive psychologists out there - is it possible to improve your concentration and have that not improve learning?  I can't imagine how that happens.  If you go from not being able to read 2 pages at a time to suddenly reading chapters at a time, how is that not enhanced cognitive performance?  If you go from staring out the window all day and daydreaming to being able to focus on what the teacher is saying how will that not lead to an improved outcome?  The idea that improved attention - a central factor in human cognition will not affect anything over time suggests to me that the measures being used for follow up are not very robust or that this is a skewed sample of opinion.   

For the purpose of cognitive enhancement, the typical users are students trying to gain an edge by increasing their study time.  Anyone who has experienced college and professional school realizes that here is a large amount of information to be mastered and it is not presented in an efficient way.  I can never recall a professor who advised us of the important guideposts along the way or gave us any shortcuts.  The usual message is study all of this material in depth every day or you will fall behind.  That approach in general is consistent with gaps in the ability to study either through the normal course of life or the competition for intellectual resources by 3 or 4 other professors who regard their courses as important.  That typically results in a pattern of cramming for specific key exams.  Although I have not seen any specific studies, stimulant medications are generally used for this purpose and in many cases the use is widespread.  There is a literature on the number of college students who may be feigning ADHD symptoms in order to get a prescription and that number could be as high as 50% (4,5). 

What  about the issue of stimulants acting as a smart pill in people who don't have ADHD?  In the most comprehensive review I could find on the subject (6) the authors review laboratory studies and conclude that in those settings stimulants enhance consolidation of declarative learning to varying degrees, had mixed effects on working memory, and mixed effects on cognitive control.  On 8 additional tests of executive function, the authors found that stimulant medication enhance performance on two of those tests - non-verbal fluency and non-verbal intelligence.  They have the interesting observation that small effects could be important in a competitive environment.  Their review also provides an excellent overview of the epidemiology of stimulant use on campuses that suggests that the overall prevalence is high and the pattern of use is consistent with cramming for exams.  They cite a reference that I could not find (7) that was a reanalysis of NSDUH data suggesting that as many as 1 in 20 stimulant users may have a problem with excessive use and dependence.     

Getting back to the theme of the Nature commentary, it is ironic that the smart pill theme is being called into question when it was the subject of a Nature article years earlier advocating for the use of cognitive enhancement.  In that article Greely, et al come to the somewhat astounding conclusion: 

"Based on our consideration, we call for a presumption that mentally competent adults should be able to engage in cognitive enhancement using drugs."

They arrive at that conclusion by rejecting three arguments against this practice.  Those arguments include that it is cheating, it is not natural and it is drug abuse.  Their rejection of the cheating argument is interesting because they accept the idea that performance enhancing drugs (PEDS) in sports is cheating.  They reject that in cognitive enhancement claiming that there would need to be a set of rules outlining what forms of enhancement would be outlawed and what would not (e.g. drugs versus tutors).  To me that seems like a stretch.  I think that sports bodies select performance enhancing drugs as a specific target because it clearly alters body physiology in a way that cannot be altered by any other means.  There is also plenty of evidence that the types of PEDS are dangerous to the health of athletes and associated with deaths.  Their conclusion about drug abuse: "But drugs are regulated on a scale that subjectively judges the potential for harm from the very dangerous (heroin) to the relatively harmless (caffeine).  Given such regulation the mere fact that cognitive enhancers are drugs is no reason to outlaw them."   That is a serious misread of the potential addictive properties of stimulants and the previous epidemics that occurred when the drugs were FDA  approved for weight loss, the epidemic of street use in the 1970s and the current and ongoing epidemic of meth labs and methamphetamine use throughout much of the USA.

These authors go on to outline four policy mechanisms that they believe would "support fairness, protect individuals from coercion, and minimize enhancement related socioeconomic disparities."  At first glance these lofty goals might seem reasonable if society had not already had in depth experience with the drugs in question.  The clearest example was the FDA approved indication of amphetamines for weight loss.  What could be a more equitable application than providing amphetamines to any American who wanted to use them for weight loss?  The resulting epidemic and reversal of the FDA decision is history.  A similarly equitable decision to liberalize opioids in the treatment of chronic pain had resulted in another epidemic of higher lethality due to differences in the toxicology of opioids and amphetamines. 

The contrast between these two commentaries in Nature also highlight a couple of the issues about the way medical problems and treatment is portrayed in the media.  This first is that you can't have it both ways.  Quoting a researcher or two out of context does not constitute an accurate assessment of the science involved.   Some of the authors in the first commentary are highly respected researchers in cognitive science and they clearly believe that cognitive enhancement occurs and it should be widely applied.  Nature or any other journal cannot have it both ways.  A more realistic appraisal of the problem is addressed in reference 6.   The second issue is that in both cases the authors seem blind to the addictive properties of stimulants and they are ignorant of what happens when there is more access as exemplified by the FDA misstep of approving stimulants for weight loss.  Do we really need a new epidemic to demonstrate this phenomenon again?  Thirdly, all of this comes paying lip service to non - medication strategies for cognitive enhancement.  We can talk about the importance of adequate sleep - a known cause of ADHD like symptoms and if we are running universities and workplaces in a manner that creates sleep deprived states, the next step is reaching for pills to balance an unbalanced lifestyle.  The new rules for residency training are a better step in the right direction.  Fourth, college is a peak time for alcohol and substance use in the lives of most Americans.  These substances in general can lead to a syndrome that looks like ADHD.  It is highly problematic to make that diagnosis and provide a medication that can be used in an addictive manner.  It is also highly problematic to think that treating an addicted person with a stimulant will cure them of the addiction and yet it happens all of the time.

There is plenty of evidence to suggest that cognitive enhancement is cheating.   Much of my career has been spent correcting the American tendency of trying to balance one medication against another and using medications to tolerate a toxic lifestyle or workplace.  It does not work and the current group of medications that are being put forward as cognitive enhancers are generally old drugs with bad side effect profiles particularly with respect to the potential for addiction.

If you want safe cognitive enhancers that can be made widely available, they have not been invented yet.  

George Dawson, MD, DFAPA




References:

1: Sharpe K. Medication: the smart-pill oversell. Nature. 2014 Feb 13;506(7487):146-8. doi: 10.1038/506146a. PubMed PMID: 24522583.

2: Greely H, Sahakian B, Harris J, Kessler RC, Gazzaniga M, Campbell P, Farah MJ.

Towards responsible use of cognitive-enhancing drugs by the healthy. Nature. 2008 Dec 11;456(7223):702-5. doi: 10.1038/456702a. Erratum in: Nature. 2008 Dec 18;456(7224):872. PubMed PMID: 19060880.

3: Feldman HM, Reiff MI. Clinical practice. Attention deficit-hyperactivity disorder in children and adolescents. N Engl J Med. 2014 Feb 27;370(9):838-46. doi: 10.1056/NEJMcp1307215. PubMed PMID: 24571756.  

4: Green P, Lees-Haley PR, Allen LM., III The word memory test and the validity of neuropsychological test scores. J Forensic Neuropsychol. 2002;2:97–124. doi: 10.1300/J151v02n03_05

5: Suhr J, Hammers D, Dobbins-Buckland K, Zimak E, Hughes C.  The relationship of malingering test failure to self-reported symptoms and neuropsychological findings in adults referred for ADHD evaluation.  Arch Clin Neuropsychol. 2008 Sep; 23(5):521-30.

6: Smith ME, Farah MJ. Are prescription stimulants "smart pills"? The epidemiology and cognitive neuroscience of prescription stimulant use by normal healthy individuals. Psychol Bull. 2011 Sep;137(5):717-41. doi: 10.1037/a0023825. Review. PubMed PMID: 21859174 

7: Kroutil LA, Van Brunt DL, Herman-Stahl MA, Heller DC, Bray BM, Penne MA. Nonmedical use of prescription stimulants in the United States. Drug and Alcohol Dependence. 2006; 84:135–143.10.1016/j.drugalcdep.2005.12.011 [PubMed: 16480836]

Is the FDA objective enough to assess treatments in psychiatry - or is this just politics as usual?

The American Psychiatric Association (APA) feed posted a link to this FDA news release regarding a new biological test for Attention Deficit Hyperactivity disorder.  The device is essentially a quantitative EEG (QEEG) machine.  The QEEG heyday was back in the mid 1980s to 1990's.  Devices were designed that could take the standard output of an EEG montage and look at the frequency bands and how that activity fluctuated topographically within the individual.  There were two major manufacturers at the time and both of those technologies allowed for a comparison of the subjects QEEG with a standardized groups.  The difference could be determined as a t or z score and that was plotted relative to the electrode placements.  The final analysis would yield maps consisting of frequencies and mathematical operations on those frequencies.

There were several articles on this methodology including an impressive article in Science on the diagnostic capabilities of these instruments.  One manufacturer provided an algorithm of clinical features and EEG features that purported to diagnose major psychiatric disorders.  You could actually analyze the data both ways - with or without the clinical features.  There was enthusiasm to the point that a new psychiatric subspecialty in electrophysiology was made to meet the requirements of psychiatrists who wanted to use QEEG technology.

In 1988, I was so impressed with the technology that I approached a potential employer and struck a bargain that I would take a salary cut if they would buy me the machine and the deal was struck.  I was fortunate enough to be affiliated with a certified electrophysiology lab with an outstanding electrophysiologist and EEG technologists.  This was critical in order to collect standardized data and select numerous 2 second epochs of EEG data for computerized analysis.  The epochs had to be completely free of artifact in order to provide valid data for analysis and anywhere from 30 to 60 of these epochs needed to be selected per patient.

If you think about it for more than a few minutes, what is wrong with the idea that EEG frequencies should point to a specific psychiatric diagnosis?  The short answer is a lack of specificity.  There are literally hundreds of conditions that can lead to fast or slow frequencies including normal fluctuations of conscious states.  During my QEEG work we had to collect EEG epochs for analysis in the "eyes closed but alert" state.  Quantitative EEGs can demonstrate significant fluctuation in that state.

After several hundred QEEGs with and without the computerized algorithm, it was apparent that the diagnostic abilities of QEEG were low.  There were literally a handful of analyses that seemed to match the clinical diagnosis and at that point we shut down the project.  As far as I can tell from their web site, that company no longer sells a QEEG machine claiming to make psychiatric diagnoses.

I have not been able to locate the specific reference for this FDA approval.  The FDA press release states:

"In support of the de novo petition, the manufacturer submitted data including a clinical study that evaluated 275 children and adolescents ranging from 6 to 17 years old with attention or behavioral concerns. Clinicians evaluated all 275 patients using the NEBA System and using standard diagnostic protocols, including the Diagnostic and Statistical Manual of Mental Disorders IV Text Revision(DSM-IV-TR) criteria, behavioral questionnaires, behavioral and IQ testing, and physical exams to determine if the patient had ADHD. An independent group of ADHD experts reviewed these data and arrived at a consensus diagnosis regarding whether the research subject met clinical criteria for ADHD or another condition. The study results showed that the use of the NEBA System aided clinicians in making a more accurate diagnosis of ADHD when used in conjunction with a clinical assessment for ADHD, compared with doing the clinical assessment alone."

From ClinicalTrials.gov that appears to be this registered clinical trial.  No results are reported and there are no publications in peer reviewed journals that I can find.  The concerns about this technology should be apparent from the history outlined in the above narrative and the same application suggested by the FDA.  This is not a diagnostic procedure but one that is a supplement to the clinical evaluation for ADHD.  It reminds me what Russell Barkley - noted ADHD expert and scholar said in a seminar I attended last fall.  There are no gold standard tests for ADHD any more than there are for any other problems of executive function.  He pointed out that hours of neuropsychological testing (he is a neuropsychologist) is no more accurate than standard ADHD checklists.  Neuropsychological testing is important because of the high prevalence of learning disorders in ADHD.

My prediction at this point (pending an actual published research paper) is that this QEEG machine will not be that clinically useful and if it is a question of neuropsychological testing versus the QEEG, neuropsych testing should be the the option because it can detect and allow for treatment planning for any associated learning disorders and QEEG cannot. One of the risks here in an age where insurance companies deny diagnostic costs is that neuropsychological testing is denied and the QEEG substituted depending on cost.  That would not allow for the recognition or treatment planning for a learning disorder.

The larger question is how competent the FDA is to make decisions on devices for psychiatric disorders?  The FDA came out with a notice in 2011 that electroconvulsive therapy devices may need to be reclassified (Class II to Class III) resulting in the need for additional testing, clinical trials, and regulation.  That occurred after two generations of psychiatrists were trained on the current devices and have clinically demonstrated that it is a safe, effective and in many cases life saving therapy.  They completed their own study and meta-analyses and it is unclear to me what they concluded.  I consider the FDA web site to essentially be unnavigable.  Available information in the psychiatric literature suggests that they are still is the process of coming up with a formula for reclassification of ECT devices to a more restrictive category and that their analysis of the efficacy of ECT may have been seriously underestimated.  The concern of the authors is that reclassification will restrict availability of ECT to patients who have clear indications for its use much in the same way that poor Medicare reimbursement restricts the availability in some hospitals now.

The even larger question is there some kind of systematic bias operating here?  Both the ECT and QEEG decisions seem mismatched with the available science and clinical experience.  The FDA has the appearance of transparency, but you can never find what you need in the thousands of web pages that are linked to the agency.  In the ECT example, I could not find a clear statement, vote or conclusion about the ECT decision until I read the article by Weiner, at al.  In the case of the QEEG device there is no publication of the study supporting its use.  Independent review suggests that there have been no advances in the past 16 years.

George Dawson, MD, DFAPA


FDA Executive Summary.  Meeting to Discuss the Classification of Electroconvulsive Therapy (ECT) Devices.  January 27-28, 2011.

Weiner R, Lisanby SH, Husain MM, Morales OG, Maixner DF, Hall SE, Beeghly J,Greden JF; National Network of Depression Centers. Electroconvulsive therapy device classification: response to FDA advisory panel hearing and recommendations. J Clin Psychiatry. 2013 Jan;74(1):38-42. doi:10.4088/JCP.12cs08260. PubMed PMID: 23419224.

Sand T, Bjørk MH, Vaaler AE. Is EEG a useful test in adult psychiatry? Tidsskr Nor Laegeforen. 2013 Jun 11;133(11):1200-1204. English, Norwegian. PubMed PMID: 23759782.

Nuwer M. Assessment of digital EEG, quantitative EEG, and EEG brain mapping: report of the American Academy of Neurology and the American Clinical Neurophysiology Society. Neurology. 1997 Jul;49(1):277-92. Review. PubMed PMID: 9222209.

"E. On the basis of current clinical literature, opinions of most experts, and proposed rationales for their use,QEEG remains investigational for clinical use in postconcussion syndrome, mild or moderate head injury, learning disability, attention disorders, schizophrenia, depression, alcoholism, and drug abuse." (from Nuwer 1997)