An Unusual Molecule

Fenethylline

In the course of addiction practice it is common to run across unusual compounds typically being used for their intoxicating properties.  That happened to me recently when I encountered the compound fenethylline.  Fenethylline was apparently invented for use as a stimulant in Attention Deficit-Hyperactivity Disorder and some of the conditions that were precursors to this diagnosis.  I have read a lot of that literature and had never encountered it.  The interesting property of this chemical is that it is cleaved in vivo to theophylline and amphetamine.  Theophylline is one of a class of coumpounds called methyl xanthines that most physicians in my era were familiar with from the treatment of asthma and exacerbations of chronic obstructive pulmonary disease.  They proved to be weak medications and although some sources list them as tertiary agents today use is not very likely.  This medication is proof that medicine evolves based on what happens with real world applications.  This pill for the most part has been replaced by inhaled corticosteroids alone or inhaled corticosteroids in combination with long acting inhaled beta agonist medications.  Theophylline is a non-addicting medication that can produce side effects very similar to excessive caffeine use in a number of patients.

Amphetamine is different and is in a number of preparations for ADHD.  Many of these preparations are FDA approved for that application.  Amphetamine is a potentially addicting drug and is a Schedule II N stimulant on the schedule of controlled substances indicating a high high potential for abuse or dependence.  Fenethylline is a Schedule I compound meaning that there is no accepted medical use, high risk for abuse and a lack of safety when used under medical supervision.  It has been a Schedule I compound since 1981.

In the medical literature problems with fenethylline were noted as early as the the 1960s with the first paper on addiction published in 1965 (1).  It was apparently synthesized in 1961.  It was listed as a substance of concern by the World Health Organization in 1986 (2).  There was a paper the same year pointing out that it had been in use for 21 years at that point and it appeared to have less abuse potential than amphetamine. More recent case reports have been published on the issue of psychosis and myocardial infarction from using the drug.  The real issue that has surfaced in the last several years has been the addictive potential and the use of revenues generated from this drug being used to fund terrorist operations and possible the war in Syria.

Van Hout and Wells (7) track the illicit manufacture of fenethylline and synthetic amphetamine type stimulants (ATS) in the Middle East.  The manufacture of Captagon ( a former brand name for fenethylline) started in the early 2000s in Southeastern Europe and it was transported to the Arabian Peninsula.  The name branded medication did not contain fenethylline but an array of amphetamine and caffeine like stimulants as well as antibiotics.  Lebanon became a major supplier of the drug but eventually Syria took over in about 2013.  In 2015 about 48 million pills of Captagon were confiscated en route from Syria to various Middle Eastern locations.

The Captagon tablets themselves sell for $3 to $20 each and are thought to serve two purposes - a stimulant for soldiers engaged in the military who need to be alert and aggressive and as a revenue source for funding the war.  They are widely available on the Arabian Peninsula.

A brief review of the pharmacology of fenethylline (6) suggests that the compound is more lipid soluble and have better brain access than amphetamine products.  All of the currently available medical sources seem to suggest that it is less toxic than amphetamine, but also considerably weaker.  The literature is limited but the reasons for why it has attained a great deal of value in the Middle East do not seem perfectly clear.  The rationale for synthesizing the original compound is also not very clear.  There has always been some folklore that methylxanthines like caffeine and theophylline would have a stimulant like effect on persons with ADHD.  Reviews of that phenomenon have found very little to back it up (8,9).          

I post this here as another curious note in terms of another addictive drug that appears to be unique to a certain part of the world.  As usual, wherever an addictive compound is found there will be people there to profit from it.      

George Dawson, MD, DFAPA



References:




1: Grahmann H, Reimer F.  Captagon as an addicting drug.  Nervenarzt.  1965 May; 36: 227-8. German. PubMed PMID: 14305717.

2: Keup W. Use, indications and distribution in different countries of thestimulant and hallucinogenic amphetamine derivatives under consideration by WHO. Drug Alcohol Depend. 1986 Jun;17(2-3):169-92. PubMed PMID: 2874968.

3: Kristen G, Schaefer A, von Schlichtegroll A. Fenetylline: therapeutic use,misuse and/or abuse. Drug Alcohol Depend. 1986 Jun;17(2-3):259-71. PubMed PMID: 3743408.

4: Al-Imam A, Santacroce R, Roman-Urrestarazu A, Chilcott R, Bersani G, Martinotti G, Corazza O. Captagon: use and trade in the Middle East. Hum Psychopharmacol. 2016 Oct 21. doi: 10.1002/hup.2548. [Epub ahead of print] PubMed PMID: 27766667. 

5: Khanra S, Sen S. Pharmacoterrorism: We should be worried. Asian J Psychiatr. 2016 Aug;22:83. doi: 10.1016/j.ajp.2016.05.002. PubMed PMID: 27520902. 

6: Katselou M, Papoutsis I, Nikolaou P, Qammaz S, Spiliopoulou C, Athanaselis S. Fenethylline (Captagon) Abuse - Local Problems from an Old Drug Become Universal. Basic Clin Pharmacol Toxicol. 2016 Aug;119(2):133-40. doi: 10.1111/bcpt.12584. Review. PubMed PMID: 27004621. 

7: Van Hout MC, Wells J. Is Captagon (fenethylline) helping to fuel the Syrian conflict? Addiction. 2016 Apr;111(4):748-9. doi: 10.1111/add.13262. PubMed PMID: 26787140.

8: Hughes JR, Hale KL. Behavioral effects of caffeine and other methylxanthines on children. Exp Clin Psychopharmacol. 1998 Feb;6(1):87-95. Review. PubMed PMID: 9526149. 

9: Stein MA, Krasowski M, Leventhal BL, Phillips W, Bender BG. Behavioral and cognitive effects of methylxanthines. A meta-analysis of theophylline and caffeine. Arch Pediatr Adolesc Med. 1996 Mar;150(3):284-8. PubMed PMID: 8603222.




Attributions

Fenetylline structure was obtained from ChemSpider.

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.

Did The FDA Forget About America's First Amphetamine Epidemic?

That was the first thought I had when I read through the FDA release on the approval of Vyvanse for "binge-eating disorder".  I thought of the rotation I did on the Eating Disorder service at the University of Minnesota with some of the top experts in anorexia nervosa and bulimia.  In those days the residents admitted the patients and also rotated through the outpatient clinic where they saw new cases of eating disorders and developed treatment plans with the supervision of the attendings.  We talked about a lot of binge eating, since binge eating was a critical aspect of bulimic behavior.  ""Do you ever consume an amount of food large enough that it might be embarrassing if someone else found out?" and getting the details of that specific behavior was one of my standard interview questions.  It was clear that the binge eating of bulimia was a volume and rate task.  I would hear about large amounts of diet soda and popcorn being consumed in order to complete the cycle.

In the intervening 2 decades the only real changes was the addition of bulimia nervosa a composite of bulimic and anorexic behaviors.  That is until the advent of Binge-Eating Disorder in DSM-5.  In addition to a binge definition not much different from the one I used in 1984 eating an amount of food that is "definitely larger than what most people would ingest in the same period and similar circumstances" there is loss of control, and behavioral specifiers for rapidity, physical sensations, appetite, and psychological reactions to the binge eating.  Marked distress needs to occur and it cannot be part of another eating disorder.  The time specifier is that it needs to occur at least once a week for 3 months.  A summary of the FDA release about the indication states:

 “Binge eating can cause serious health problems and difficulties with work, home, and social life,” said Mitchell Mathis, M.D., director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “The approval of Vyvanse provides physicians and patients with an effective option to help curb episodes of binge eating."   

The DSM-5 has a point prevalence estimate of 1-1.5% in women with a peak in late adolescence and early adulthood.  That same section in the DSM-5 suggests that the course is variable:

"However, over longer-term follow-up, the symptoms of many individuals appear to diminish with or without treatment, although treatment clearly impacts outcome. Periods of remission longer than 1 year are associated with better long-term outcome." (DSM-5 p 351-352)

As far as I can tell, the evidence supporting the fast tracked application for Vyvanse is a typical 8 week clinical trial that looked at remission and reduction in binge eating rates in a multicenter study of 255 individuals (1).  Both the 50 and 70 mg doses were effective.  The publication of the research coincides fairly closely with the FDA release.  Searching through the FDA web site reveals no information about the opinion of a Scientific Committee and whether there was any consensus on the decision or concerns about the addictive potential of the drug.  

The pharmacology of the Vyvanse is interesting.  It is a prodrug - lisdexamfetamine that is a conjugate of lysine and amphetamine.  After it is absorbed into the circulation it is hydrolyzed to lysine and amphetamine.  There has always been some debate about whether this prodrug approach confers a decreased likelihood that the compound can be abused or used in an addictive manner.  Most addiction psychiatrists will tell you that it can and  the FDA approved package insert confirms the fact that it has significant abuse potential.   It is a Schedule II drug according to the DEA.

The lesson of the first amphetamine epidemic is that these drugs will be prescribed, to the point that there is very high demand and production of the drug.  Widespread health consequences were noted from overprescribing stimulants for questionable indications (weight loss, nasal congestion, depression, anxiety, psychosomatic complaints).  During the peak of this epidemic (1969) the total number of 10 mg amphetamine doses was about 25 million.  This was not exceeded until about 2005 and then only as a combination of amphetamine and methylphenidate.  As a psychiatry resident in the 1980s, I was still seeing obese people who had not lost a pound using very high doses of amphetamines.  The weight loss indication was subsequently banned in order to establish some limits on the overprescription of these compounds.  In other words, they were taking the drug because of an addiction rather than using it for any therapeutic effect.  It is clear that the prescription of controlled substances for diagnoses that are based on subjective findings is a recipe for epidemics of addictive drugs both in terms of total prescriptions, escalating use, and diversion.  Stimulant medications have the additional allure as possible performance enhancing drugs and are widely diverted for that purpose.

In that context, it would seem that the FDA would need to come up with a clear rationale for using a Schedule II drug to treat what may be a time limited disorder or a disorder that responds to non-medical therapies.  The complex nature of medications that have addictive potential needs to be recognized.  The prescription of these compounds takes more than rote knowledge. At the minimum there needs to be strict pharmacosurveillance on how this drug is prescribed and flags need to be in place for trends indicating that the prescriptions are starting to exceed the known prevalence of the disorder or the dose ranges are higher than recommended and/or combined with short acting stimulants.  These are all common problems seen in the overprescription of controlled substances.

Passive post marketing surveillance can no longer be considered a viable option for stopping the overprescription of controlled substances.   Waiting for intervention by law enforcement when problems have already begun is an approach from the 1960s.  In an era when data mining is commonplace, the FDA can do a lot more than get drugs out into the marketplace and wait to see what happens.         

George Dawson, MD, DFAPA

1: McElroy SL, Hudson JI, Mitchell JE, Wilfley D, Ferreira-Cornwell MC, Gao J, Wang J, Whitaker T, Jonas J, Gasior M. Efficacy and Safety of Lisdexamfetamine for Treatment of Adults With Moderate to Severe Binge-Eating Disorder: A Randomized Clinical Trial. JAMA Psychiatry. 2015 Jan 14. doi: 10.1001/jamapsychiatry.2014.2162. [Epub ahead of print] PubMed PMID: 25587645.

2: Nutt, David, Leslie A King, William Saulsbury, Colin Blakemore. Development of a rational scale to assess the harm of drugs of potential misuse. The Lancet 2007; 369:1047-1053. PMID 17382831;doi:10.1016/S0140-6736(07)60464-4

Supplementary 1:  The following graph is from Wikimedia Commons and it is public domain.  It is a derivative work of reference 2 above and a complete description is available at this link.  I could find no author to cite.

Supplementary 2:  Almost on cue I noticed the first banner ads for Binge-Eating Disorder today (2/12/2015).  It is advertised as a "real medical disorder" and is a brief informational film.  It has a spokesperson who talks about her experience with the disorder and refers the interested viewer to the company web site at BingeEatingDisorder.com.  It carefully coaches people in how to talk with their doctor.  The pharmaceutical company and manufacturer is listed at the bottom on the page.  The graphic of a pizza slice over a drawing of a brain varies in different views.  I don't know exactly what that means.  It suggests psychological therapies for B.E.D. and does not mention Vyvanse.  But let's face it - when people read there is a pill for their eating problem and it is an amphetamine - how many people will be asking for the psychological therapies?

ADHD and Crime

There has been a lot of commentary on the NEJM article on the association between stimulant treatment of Attention Deficit Hyperactivity Disorder (ADHD) and less crime in a cohort of patients with ADHD.  Two of my favorite bloggers have commented on the study on the Neuroskeptic and Evolutionary Psychiatry blogs.  As a psychiatrist who treats mostly patients with addictions who may have ADHD and teaches the subject in lectures - I thought that I would add my opinion.

Much of my time these days is spent seeing adults who are also being treated for alcoholism or addiction. I also teach the neurobiological aspects of these problems to graduate students and physicians.  In the clinical population that I work with - ADHD is common and so is stimulant abuse/dependence and diversion.  Cognitive enhancement is a widely held theory on college campuses and in professional schools.  That theory suggests that you can study longer, harder, and more effectively under the influence of stimulants.  They are easy to obtain.  Stimulants like Adderall are bought, sold, and traded.  It is fairly common to hear that a feeling of enhanced cognitive capacity based on stimulants acquired outside of a prescription is presumptive evidence of ADHD.  It is not.  It turns out that anyone (or at least most people) will have the same experience even without a diagnosis of ADHD.

There is very little good guidance on how to treat ADHD when stimulant abuse or dependence may be a problem.  Some literature suggests that you can treat people in recovery with stimulants - even if they have been previously addicted to stimulants.  Anyone making the diagnosis of ADHD needs to makes sure that there is good evidence of impairment in addition to the requisite symptoms.  Ongoing treatment needs to assure that the stimulants are not being used in an addictive manner.  I would define that as not accelerating the dose, not taking medications for indications other than treating ADHD (cramming for an exam, increased ability to tolerate alcohol, etc), not attempting to extract, smoke, inject, or snort the stimulant, not obtaining additional medication from an illegal source, and not using the stimulant in the presence of another active addiction.  Addressing this problem frequently requires the use of FDA approved non stimulant medication and off-label approaches.

With the risk of addiction that I see in a a population that is selected on that dimension, why treat ADHD and more specifically why treat with medications?  The literature on the treatment of ADHD is vast relative to most other drugs studied in controlled clinical trials.  There have been over 350 trials and the majority of them are not only positive but show very robust effects in terms of treatment response.  The safety of these medications is also well established.

Enter the article from the NEJM on criminality and the observation that stimulants treatment may reduce the criminality rate.  This was a Swedish population where the research team had access to registries containing data on all persons convicted of a crime, diagnosed with ADHD, getting a prescription for a stimulant, and to assign 10 age, sex, and geography matched controls to each case.  Active treatment was rather loosely defined as any time interval between two prescriptions as long as that interval did not exceed six months.  The researchers found statistically significant reductions during the time of active treatment for both men (32%) and women (41%).      

I agree that this is a very high quality article from the standpoint of epidemiological research - but my guess is the editors of the NEJM already knew that.  This study gets several style points from the perspective of epidemiological research.  That includes the large data base and looking for behavioral correlates of another inactive medication for ADHD - serotonin re-uptake inhibitors or SSRIs.  There is a robust correlation with stimulants but not with self discontinued SSRIs.  They also analyzed the data irrespective of the order of medications status to rule out a reverse causation effect (treatment was stopped because of criminal behavior) and found significant correlations independent of order.

Apart from the usual analysis clinical and researchers in the field ranging from neurobiologists to researchers doing long term follow up studies do not find these results very surprising.  The Medline search below gives references of varying quality dating back for decades.  The pharmacological treatment certainly goes back that far.  The accumulating data suggests that where the disorder persists, it requires treatment on an ongoing basis.  A limited number of studies suggest that cognitive behavioral therapy (CBT) may be useful for adults with ADHD but not as useful for children or adolescents.  The practice of "drug holidays" prevalent not so long ago - no longer makes sense when the diagnosis is conceptualized as a chronic condition needing treatment to reduce morbidity ranging from school failure to decreased aggression to better driving performance.

One of the typical criticisms of epidemiological research of this design is that association is not causality, I think it is time to move beyond that to what may be considered causal.  In fact, I think it may be possible at this time to move beyond the double blind placebo controlled trial to an epidemiological standard and I will try to pull together some data about that approach.

George Dawson, MD, DFAPA

Lichtenstein P, Halldner L, Zetterqvist J, Sjölander A, Serlachius E, Fazel S, Långström N, Larsson H. Medication for attention deficit-hyperactivity disorder and criminality. N Engl J Med. 2012 Nov 22;367(21):2006-14. doi: 10.1056/NEJMoa1203241.

Criminality and ADHD:  Medline Search