Medical Cannabis Does Not Prevent Opioid Overdoses

The political aspects of medical cannabis are undeniable. The legalization of cannabis for recreational purposes had no traction with American politicians or voters until it was promoted as a miracle drug.  With that widespread promotion medical cannabis is now legal in 33 states and recreational cannabis is legal in ten.  The legalization arguments also suggested that the US was behind other countries of the world when there are only two countries – Canada and Uruguay – where it is completely legal for medical or recreational sale and purchase.  In the world, 22 of 195 countries have legalized medical cannabis with widely varying restrictions on its use. The Netherlands is often cited as an example of recreational cannabis use, but most Americans don’t realize that it is illegal for recreational use and tolerated for use and sale only in specially licensed coffee shops.  The promotion of cannabis as a solution to the opioid overuse and chronic pain problems can be seen as an extension of the political arguments for legalization that outpace any science to back them up.

There was probably no greater hype about the purported benefits of medical cannabis than early data suggesting that it might decrease the rate of opioid overdoses (1). The sequence of events was supposed to be opioid users tapering off of opioids or using lower equivalent amounts because of medical cannabis use.  The original study covered the time period from 1999-2010 and suggested that states with medical cannabis laws had a lower mean opioid overdose mortality and that the annual rates of overdose progressively decreased over time.  The authors conclusion was:  “Medical cannabis laws are associated with significantly lower state-level opioid overdose mortality rates.”

Despite the usual caveats suggested by the authors in the original study the results of that study were heavily hyped by all cannabis promoters as was the discussion of many Internet forums.  The lay press, public, and politicians saw it as another reason to promote medical cannabis and recreational cannabis by association.

A study came out today in PNAS (2), that is an extension of the original data and it no longer comes to the same conclusion.  In this new study the authors replicated the opioid mortality estimates from the original study but when the data was extended from 2010 to 2017 – the improved opioid overdose mortality rates not only did not stay constant but they reversed themselves to that they were now on the average from -21% to +23%.  They provide an even more valuable analysis of this effect as spurious rather than a true positive or negative effect based on the low penetration of medical cannabis in the population at large (2.5%).  The authors focus on the problem of ecological fallacy – that is conclusions about individuals are drawn from aggregate data across the entire population.They point out that the states with the medical cannabis laws have a number of characteristics separating them from other states.  A recent good example of this fallacy was the New England Journal of Medicine (3,4) report that per capita chocolate consumption correlated with the number of Nobel Laureates in a particular country.  

This is a valuable lesson in scientific analysis. The political approach to the problem is all that most of the public sees. That approach is to grab any information that seems to agree with your viewpoint and run with it.  Big Cannabis and cannabis promoters have been doing this for almost 20 years now. The process of science on the other hand is slower and more deliberate.  It is not a question of a right answer but a dialogue that hopefully produces the right pathway. The authors of this study have added a lot to the dialogue about cannabis but also statistics and how statistical descriptions may not be what they seem to be. 

George Dawson, MD, DFAPA

References:

1: Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668–1673. doi:10.1001/jamainternmed.2014.4005 (full text)

2:  Shover CL, Davis CS, Gordon SC, Humphreys K.    Association between medical cannabis laws and opioid overdose mortality has reversed over time.  First published June 10, 2019 https://doi.org/10.1073/pnas.1903434116  (full text)

3: Messerli FH. Chocolate consumption, cognitive function, and Nobel laureates. NEngl J Med. 2012 Oct 18;367(16):1562-4. doi: 10.1056/NEJMon1211064. Epub 2012 Oct 10. PubMed PMID: 23050509.

4:  Pierre Maurage, Alexandre Heeren, Mauro Pesenti, Does Chocolate Consumption Really Boost Nobel Award Chances? The Peril of Over-Interpreting Correlations in Health Studies, The Journal of Nutrition, Volume 143, Issue 6, June 2013, Pages 931–933, https://doi.org/10.3945/jn.113.174813


Attribution:

Above figure is from the original article (reference 2): "This open access article is distributed under Creative Commons Attribution-Non Commercial No Derivatives License 4.0 (CC BY-NC-ND).y"  See this link for full conditions of this license.

Lithium and Pregnancy - The Latest From the NEJM

Lithium and pregnancy have always been a major concern for psychiatrists, obstetricians, and of course women who need to take the medication for mood stabilization.  In the Lithium Encyclopedia (published in 1983) - there is a chapter on the physiological effects of pregnancy and how that potentially affects lithium balance and a separate chapter on teratogenesis.  That chapter describes the Lithium Baby Registry that was established in 1970 to collect information on the effects of lithium in pregnancy.  In the first 10 years, 225 infants exposed to lithium were described and 25 had congenital malformations.  Of these births 18/25 had cardiovascular abnormalities including Ebstein's anomaly, 7 were stillborn, 2 had Down's syndrome and 1 had intracerebral toxoplasmosis.  The results suggested that lithium was a cardiovascular teratogen, but there was a question of reporting bias.  That is, results consistent with the study concern about lithium being a teratogen were more likely to be reported than normal births.  

Those references set the knowledge about lithium and  pregnancy for all residents trained in my era in the late 1980s.  The standard question by attendings and on examinations was: "What is the cardiac anomaly associated with intrauterine exposure to lithium?".  The answer was Ebstein's anomaly.  The follow up question was expected: "And what is Ebstein's anomaly?"  In those days the short answer was downward displacement of the tricuspid valve into the right ventricle.  Today Ebstein anomaly (no longer a possessive) is described in greater detail. A modern reference describes the extension of the tricupsid valve into the right atrium to the extent that most of the functional chamber chamber is collapse to a very small volume.  In some cases it is collapsed to the right ventricular outflow tract.  The downward valve displacement is due to a number of morphological abnormalities in the tricuspid valve.  The myocardium is also abnormal because the valve tissue has failed to completely separate from the myocardium during fetal development - a process called delamination.  That is associated with a thin and poorly contractile myocardium and poor right ventricle performance. There are several associated cardiac abnormalities including ventricular septal defect, patent foramen ovale, patent ductus arterious, and accessory conduction pathways that can lead to arrhythmias.  The associated clinical syndromes of cyanosis, congestive heart failure and arrhythmia can occur in infancy to adulthood depending on the degree of anatomical disruption.  The complications can be fatal at any age (2).

Ebstein abnormality is a preventable complication and one that must be avoided.  In real life that is easier to say than do.  In a controlled hospital or clinic environment it is a very straightforward process to take a history and determine the obstetric history and last menstrual period.  Urine and serum pregnancy tests can be done for confirmation.  The best advice to physicians in this situation is to treat very woman of childbearing age as if they were pregnant until proven otherwise.  In my experience life is less regimented.  There are lapses in contraception and planning that lead to pregnancies in women taking lithium who know that exposure to the infant is an avoidable risk.  Many of these women are on lithium maintenance.  Since lithium remains a mainstay of treatment for bipolar disorder and may be a superior agent in postpartum psychosis - the question of teratogenicity remains an important one.

There have been a number of estimates of congenital malformations due to psychiatric medications and I recently reviewed a few of them and cited extensive database references.  In one of the reviews very large databases were examined looking for major congenital malformations to lithium exposed women especially Ebstein anomaly.

The New England Journal of Medicine published another large retrospective database study of the question of lithium exposure in pregnancy and risk of cardiac malformations.  Their database involve a Medicaid cohort of 1,325,563 pregnancies over the ten year period between 2000 and 2010.  In this cohort there were cardiac malformations noted in 16 of 663 (2.4%) lithium exposed infants.  Lower rates of cardiac malformations were noted in nonexposed infants (1.15%) and lamotrigine exposed infants (1.39%).  In addition there appeared to be a dose related effect with increasing risk ratio noted with increasing doses of lithium.  For example at the dose of 600 mg or less/day the risk ratio was 1.11 but the risk ratio increased to 1.11 and 3.22 for doses of 601-900 mg/day and greater than 900 mg respectively.

The authors have a detailed report on how the cardiac malformations were determined.  They make an interesting point that a misclassification bias can occur with Ebstein anomaly.  Some clinicians may make the diagnosis of right ventricular outflow tract obstruction defects or Ebstein anomaly based on whether or not there has been a history of exposure to lithium.  That may make it more likely to misclassify Ebstein anomaly.  They provide data for the total prevalence of all cardiac malformations and cardiac malformations classified as right ventricular outflow obstruction.  They were focused on "major cardiac defects that were likely to be consequential for the infant."  The diagnostic codes had to be listed several times or associated with surgery.

The calculated prevalence of Ebstein abnormality in unexposed pregnancies was 7 cases per 100,000 live births.  They did not provide the prevalence of Ebstein anomaly in the lithium exposed due to the low number.  After a detailed analysis and analysis of possible sources of error like terminate pregnancies where lithium exposure occurred the authors conclude that lithium had a modest effect in terms of increased risk of cardiac malformations.  Their final estimate was an increased risk of 1 additional case per 100 live births if the exposure occurred early in the pregnancy.  They describe this as a modest increase in risk of cardiac malformations due to lithium.  The difference in the ratio of cardiac malformations in this study (16/663) compared with the Lithium Baby Registry (18/225) is probably due to a more rigorous methodology.

The authors looked at five sources of error in their final discussion of the results.  For clinical psychiatrists the most relevant point was that other factors affecting treatment decisions in pregnancy were not investigated.  They are considerable given that it is highly likely that the women being treated with lithium have severe mood disorders and suicide in the postpartum period in the number one cause of death.  This study can best be viewed as a study that supports current clinical practice to avoid first trimester exposure to lithium by careful screening and then planning if additional adjustments need to be made for planned pregnancies based on the trimester.  In those cases of accidental exposure, consultation with high risk obstetrics and a decision based on a detailed discussion with the patient is usually the preferred option.                 




George Dawson, MD, DFAPA




References:

1.  Jefferson JW, Greist JH, Ackerman DL. Lithium Encyclopedia for Clinical Practice.  Washington, DC; American Psychiatric Press, Inc., 1983: 264-265.

2.  Connolly HM, Qureshi, MY.  Clinical manifestations and diagnosis of Ebstein anomaly. In UpToDate,  Greutmann M, Fulton DR, Yeon SB (Accessed on June 9, 2017).

3.  Patorno E, Huybrechts KF, Bateman BT, Cohen JM, Desai RJ, Mogun H, Cohen LS, Hernandez-Diaz S. Lithium Use in Pregnancy and the Risk of Cardiac Malformations. N Engl J Med. 2017 Jun 8;376(23):2245-2254. doi: 10.1056/NEJMoa1612222.

Are Hallucinogens The New Miracle Drugs?

See Attribution 1 for full reference

Steve Jobs:  "Taking LSD was a profound experience, one of the most important things in my life.  LSD shows you that there's another side to the coin, and you can't remember it when it wears off, but you know it.  It reinforced my sense of what was important - creating things instead of making money, putting things back into the stream of history and of human consciousness as much as I could."  (ref 1)

Woodstock (Chip Monck):  "To get back to the warning that I received. You may take it with however many grains of salt that you wish. That the brown acid that is circulating around us isn't too good. It is suggested that you stay away from that. Of course it's your own trip. So be my guest, but please be advised that there is a warning on that one, OK?" (ref 2)




Warning: The final few paragraphs of this post contain language that some may find offensive.  I included it for a reason.   In 30 years of practice and in my real life - I have found that many people talk this way.  If profanity offends you don't read the end of this post.



Everywhere I turn these days - whether it is a blog or more traditional media I am struck by the same stories on hallucinogens.  If you believe what you read out there, hallucinogens are magical drugs in that they are almost totally benign, consciousness expanding, and they can treat your anxiety or your depression.  They have been actively discriminated against like other illegal drugs and that is the only reason we have not done the research to prove that they can treat many problems.  Back in the 1970's we would have said that "The Man" is restricting access to valuable consciousness expanding drugs and if "The Man" was overthrown - the world would be a much better place.  I have briefly reviewed the same lines of rhetoric that occur with cannabis.  I have not heard similar arguments with ketamine, probably because fewer people have experience with it and it is a more difficult drug to use, even in a medical setting where the drug has a known concentration and purity.

Hallucinogens are a diverse set of compounds with a number of analogues of the parent compounds for each basic structure.  The DSM-5 does very little in terms of organizing the category other than saying that it might make sense to classify the dissociative hallucinogens like PCP and ketamine as a separate category from more traditional hallucinogens like LSD.  The DSM-5 does very little to attempt to classify the wide array of hallucinogens that are available at this point in time.  Some authors (3-6) use the term serotonergic or classic psychedelics such as LSD, DMT, and psilocybin (and see above graph).  I think it makes sense to classify any drug taken for the express purpose of creating hallucinations - a hallucinogen.  Drugs with secondary hallucinatory effects like alcohol, cannabis, and stimulants remain in unique categories because they can all cause hallucinations but they are generally not taken for that purpose,  More scientific classification approaches that are generally based on chemical structure are available in standard addiction texts.

As an addiction  psychiatrist, my experience is that hallucinogens are problematic drugs from a number of perspectives.  It is rare to see a pure hallucinogen user, at least until someone discovered that using high dose dextromethorphan (DXM) reliably produces hallucinations and delirium, is widely available, and inexpensive.  To that subgroup of patients many of them have a very difficult time stopping DXM.  The other problem with that drug is that excessive use of DXM in the predisposed person is common and the margin between the hallucinatory experience, toxicity and lethal overdose is not well characterized probably due to pharmacokinetic variability among subjects.  Reports of lethal ingestions in the medical literature are rare (5).  The hallucinogenic effect of DXM is from NMDA and PCP1 receptor antagonism.  DXM is metabolized by hepatic CYP2D6 so that other drugs that are inhibitors and poor metabolizer status may lead to unexpectedly higher levels of the compound in the plasma.  DXM  is also a serotonin reuptake inhibitor and a 5-HT1 direct agonist and can cause serotonin syndrome another potential cause of death when used with other serotonergic drugs.  PCP is another exception.  In my experience both PCP and DXM users are much more likely to use those drugs in an uncontrolled manner and addictive manner than other types of hallucinogens. There are seemingly rare but significant and in some cases fatal side effects from hallucinogens.  From a mental health standpoint, addiction specialists and general psychiatrists encounter patients with significant ongoing panic symptoms and perceptual disturbances that they attribute to the side effects of these medications.  The question is what is the frequency of these side effects and their significance?  An associated question is have there been any definitive studies?

Most of the recent epidemiology of hallucinogens has come from Krebs and Johansen.  Their 2013 study in PLOS was widely quotes in the news media as illustrating that classic hallucinogens are benign substances with little health risk.  Their work is based on the annual NSDUH survey of drug use in Americans.  They look at two small (N=192, N=156) cohorts of pure hallucinogen users in the NSDUH survey.  They outline the limited nature of this investigation based on the survey questions and the fact that this is a survey.  They cite other literature looking at people given LSD in clinical trials and other research and conclude that there is very little evidence for lasting side effects.  As an example, they could not corroborate that at least some people who taken hallucinogens have persistent problems with anxiety, panic attacks, or perceptual disturbances.  These are familiar themes in the new research on LSD noted in several of the additional references.  As a starter,  I read the articles (7-10) and came up with several unanswered questions.  Some are obvious in a technical sense and some are not so obvious.  Rather than get into a detailed critique of this and other papers, I thought I would outline what I see as missing in the claims made for the benign side effects profiles and efficacy of these drugs and look at more details in subsequent posts.


Efficacy for what?

These drugs in the broadest sense are not used to treat any specific collection of symptoms or syndromes.  Their popular indication for use has changed very little since the 1960s (3) and that is "mystical experiences, curiosity, and introspection."  At that level there is no medical indication for use.  They are being used to produce an altered state of consciousness like alcohol or any other recreational drug.  At that level the issue resembles in many ways medical cannabis, with the exception that cannabis seems to have some very preliminary evidence that it might be useful for some medical problems.  No such data exists for hallucinogens and psychedelics, but that is not for a lack of effort.  A recent meta-analysis discussed in Nature suggests that alcoholics treated with LSD are more likely to stay abstinent than those who are not.  The original experiments done in the 1970s, found no such correlation.  A recent paper in Lancet Psychiatry discusses application for the existential anxiety of the terminally ill and to facilitate psychotherapy.    So far the medical indications seem to be a bit of a stretch.  Using cannabis as the prototype, it seems that many parallel arguments are being made for hallucinogens.  From a rhetorical standpoint it is interesting that a common antipsychiatry criticism is that psychiatry has medicalized life in order to proliferate diagnoses and make more money for pharmaceutical companies.  Nobody seems to have any problems with cannabis or hallucinogen proponents medicalizing life in order to provide a useful venue for cannabis or hallucinogens.

As an adjunct for psychotherapy? 

There is a new recent review (14) of psilocybin and MDMA as assistive modalities in psychotherapy.  My read of this review is that the authors are proponents of these therapies.  They cite the lack of useful current therapies as a reason for exploring the therapeutic aspects of psychedelics.  That may be true to some extent but the usefulness of current therapies also depends on how broad the access is.  When I do a new assessment, I don't get the same global acceptance of therapy that some in the popular press suggest.  The impression I get is that the psychotherapy experience that most people get is suboptimal at best - and not because of the therapeutic modality.  It is often the technique of the therapist, economic considerations, managed care constraints, and/or the lack of any results.  The authors suggest that exploring psychedelics in these settings might offer better results and faster results.  I can't help but think about how therapy in real life, doesn't resemble what the psychotherapy in clinical trials is like.  Many people in managed care settings get two or three cursory sessions and they are discharged as doing better.  What happens if psychedelic assisted psychotherapy occurs in a managed care setting?  My guess is that the complex therapy is eliminated and the sessions where the drug is administered is emphasized.  The conditions for therapy reviewed include cancer anxiety, addiction (alcohol, tobacco and cocaine) and obsessive-compulsive disorder for psilocybin and PTSD, anxiety from life-threatening situations, and social anxiety in autistic adults for for MDMA.  There is minimal detail on the psychotherapeutic technique apart from some lengthy sessions.  Problems with blinding in controlled trials are discussed as an issue.  Lower dose psychedelics as the active placebo don't work.   Preliminary successes and speculation about the effect of the psychedelics and what they might be doing are discussed.  The main argument seems to be that there is ample reason to continue research in psychedelics.    


What can be measured?

All clinical trials in psychiatry lack objective measurements of both illness and improvement.  In the case of psychedelics some of these standard problems are still there.  Standard rating scales for anxiety and depression are used in some of these trials.  There are additional instruments such as the Altered States of Consciousness Questionnaire (ASQ) and the Psychotomimetic States Inventory (PSI).  It seems that an interest in purportedly consciousness expanding drugs may finally get some psychiatrists interested in consciousness as a dynamic multidimensional entity independent of syndrome definitions.  The problem of course is that these states are all highly subjective and resistant to classification.  It also highlights the question: "Is the psychedelic drug +/- psychotherapy supposed to target a typical syndrome of anxiety or depression or is there some other purpose, like altering the conscious state in some fundamental way?".  If that is true, we really have no idea how that can be measured or translated into therapy.  I would also suggest that it is outside the purview of physicians and psychiatrists.  If it is effective, the one aspect of psychedelic assisted therapy that I thought would be very useful was that the patient only takes two or three doses of the drug over the course of psychotherapy and does not require a maintenance treatment.

Quality of subjective measurement aside, there is nothing more annoying to me as an interested reader than reading about a rating scale or questionnaire that is not readily available.  I need to know what the specific questions are on those instruments.  The statistics of the instrument is a secondary consideration.  As far as I can tell neither the ASQ or the PSI is readily available in a readable form.  I would go so far to encourage editors to suggest that in the original analysis of rating scales, questionnaires, and inventories include the scale as it was used with all of the direct wording and how it was rated.  If that data is not included the article is essentially worthless to any clinician who talks to patients.


Are we measuring dimensions of consciousness?

I have addressed the general lack of concern over human consciousness in psychiatry and medicine in general.  Human consciousness is generally regarded as a brain determined state, but we have no idea how that state arises from the underlying neurobiology.  There are plenty of theories and there is a scientific society dedicated to the study of human consciousness.  Consciousness is a highly subjective state and that makes it very difficult to study.  Even a basic consideration of experiencing the color red can be as complex as considering that each human being (every human being has a unique conscious state) can experience the color red in a unique way.  We all may be able to agree on a basic task that requires selecting the color red from other colors,  but beyond that we can never be completely sure of how other people experience colors or other physical properties or more complicated states like pain, depression, aging, or the opposite gender.  If all that is true about human consciousness - what would we expect to happen if we are taking a drug that alters our conscious state.  For research purposes, if we alter a conscious state and we really don't have a good way to measure a baseline conscious state - how can we detect what changes.  Are we going to depend strictly on self report of whatever comes to the person's mind?


Sweeping conclusions about the lack of toxicity?

Any pro-hallucinogen article will produce a steady stream of references looking at how benign these compounds are.  There are usually quotes about millions of doses consumed and no deaths from LSD or other psychedelics.  The authors generally assume that the methodologies being quoted are adequate indications of drug safety.  These arguments fail at two levels.  First, there is evidence in the literature from reasonable sources that LSD exposure is not entirely benign.  The 1986 Danish LSD Damages Laws is a case in point.  In this study, 400 patients treated with LSD between 1960 and 1973 were followed.  154 of these patients were compensated for long term harm with 2/3 of them having severe flashbacks.  There was also one homicide, 2 suicides, and 4 suicide attempts in the group (12).  There is the question of other sources such such as the DAWN system that looks at the number of emergency department visits (ED) per day due to substance use.  This system looks at annual use of substances by 18-25 years olds, how much they use on an average day and the number of ED visits per day due to a specific category of drugs.

See Attribution 2 for full reference.

         
In terms of drug safety and pharmacovigilance, there really has not been any with these drugs.  The side effects tend to be case reports, anecdotal, from settings where there is likely a bias to under report side effects, and from carefully run clinical trials.  In some cases researchers have a defined protocol for the safe design and running of clinical trials involving psychedelic drugs (15).

Medicine or recreational drug?

Cannabis legalization was basically dead in the water until the proponents adopted a political strategy that involved selling it as a medical treatment rather than a recreational drug.  The preferred path seems to be starting with terminal illnesses or illnesses for which there are no current good treatments.  Nobody ever seems to explore the question about why the legalization question doesn't seem to carry the argument on its own merit.  The arguments for the therapeutic use of hallucinogens seems to be following that same pathway.

More rights and politics?

Some of the pro-hallucinogen literature promotes the use of hallucinogens including the legal right of people to use hallucinogens.  I have no problem at all with activists trying to influence their favorite politicians in a way that they can more easily obtain their favorite intoxicant.  I do have a problem when activists start to write medical literature from that perspective.  I also think that an additional level of disclosure is needed at the editorial level.  Authors that argue for the availability of hallucinogens (or for that matter any recreational intoxicant) should disclose that as a potential conflict of interest by specific compounds.  An example would be: "Dr. Smith supports the widespread availability of LSD for both medical and recreational use".  Explicitly stating that potential conflict of interest, is every bit as important as stating that your research has been supported by a pharmaceutical company, but it is more difficult to track.    

Is there a better way to live?

There are always philosophical and ethical considerations.  As I hope to show in a future post, philosophers generally are not too interested in telling people how to live (although there are a few notable exceptions).  Psychiatrists certainly are not interested in that either no matter how much rhetoric is out there saying otherwise.  The arguments to use or try hallucinogens are of the general form that it may improve you in some way or offer you valuable insights.  It certainly may not or in the case of many leave them with a very negative residual memory of the personal experiment or some residual symptoms.  Much of the rhetoric is the old legalization argument: "If it really is that harmless, who shouldn't I have the freedom to use it?"  Add the corollary: "It is less dangerous than tobacco and alcohol!" and you have a full scale legalization argument on your hands.  This debate has become stereotypical these days and nobody seems to ever ask the question: "Is this a reasonable way to live?"  or  "Should people get high just because we can?"  Do you really have to take a drug to expand your consciousness or can you do something else?  Focusing on only the legal aspect and the freedom to use drugs short circuits that larger question and it is a very significant question.  Moreover - if your goal is expanding your consciousness how do you know that LSD is the best way to do that?  How do you know it is just not a complete waste of time - time that you may not have to waste?

There is a phrase that is popular in the drug using vernacular and that phrase is "fucked up."  It encompasses an entire spectrum from a highly desired state of intoxication to a very dysphoric state of toxic effects, withdrawal effects, and delirium.  Interview people at either end of the spectrum and they will declare: "I am really fucked up!" with varying prosody to suggest the end of the spectrum they perceive themselves to be at that given moment.  That is assuming that they are not too delirious to speak.  Use of the term highlights how subjective drug use is as well as the full spectrum of use.  It removes any pretense that a legal intoxicant will be used primarily in a therapist's office or a room full of intellectuals focused on expanding their consciousness.    We can't use a 10 point scale with the term on either end.  We are not really treating anything.  How many days during your life can you spend "fucked up" - whether or not the intoxicant is medically dangerous to you?  Probably not too many if you expect to have a work, a social and a family life where you depend on other people and they depend on you.  Probably not too many if you live in a dangerous environment like Minnesota and you have to decide at some point that you need to be wearing enough protective clothing outdoors to prevent frostbite, exposure, and death.

Hallucinogens or psychedelics are probably not the new miracle drugs simply because they have already been sold that way and it didn't work out.  As two authors (13) closer to the history of LSD put it:

"....In all likelihood acid will continue to ravage as many people as it liberates and deceive as many as it enlightens.  Whether it will play a more significant role in the future remains a matter of conjecture, for the psychedelic experience carries the impress of a constellation of social forces that are always shifting and up for grabs.  It's not over yet."  

My only qualifier is always that people with addictions will generally do worse.



George Dawson, MD, DFAPA



References:

1:  Walter Isaacson.  Steve Jobs.  Simon & Schuster.  New York. 2011. p 41.

2: Woodstock: Music from the Original Soundtrack and More. Cotillion Records. 1970.

3:  Glennon RA.  The pharmacology of hallucinogens and designer drugs.  in Principles of Addiction Medicine, Fourth Edition.  RK Ries, DA Fiellin, SC Miller, and R Saitz (eds); Wolters Kluwer/Lippincott Williams & Wilkins; Baltimore 2009: pp 215-230.

4:  Domino EF, Miller SC.  The pharmacology of dissociatives.  in Principles of Addiction Medicine, Fourth Edition.  RK Ries, DA Fiellin, SC Miller, and R Saitz (eds); Wolters Kluwer/Lippincott Williams & Wilkins; Baltimore 2009: pp 231-240.

5:  Pechnick RN, Cunningham KA.  Hallucinogens.  in Substance Abuse: A Comprehensive Textbook, Fifth Edition.  P Ruiz, E Strain (eds); Wolters Kluwer/Lippincott Williams & Wilkins; Baltimore 2011: pp 267-276.

6:  McCann UD.  PCP/Designer Drugs/MDMA. in Substance Abuse: A Comprehensive Textbook, Fifth Edition.  P Ruiz, E Strain (eds); Wolters Kluwer/Lippincott Williams & Wilkins; Baltimore 2011: pp 277-283.

7: Krebs TS, Johansen PØ. Psychedelics and mental health: a population study. PLoS One. 2013 Aug 19;8(8):e63972. doi: 10.1371/journal.pone.0063972. eCollection 2013. PubMed PMID: 23976938; PubMed Central PMCID: PMC3747247.

8: Johansen PØ, Krebs TS. Psychedelics not linked to mental health problems or suicidal behavior: a population study. J Psychopharmacol. 2015 Mar;29(3):270-9. doi: 10.1177/0269881114568039. Epub 2015 Mar 5. PubMed PMID: 25744618. 

9: Krebs TS, Johansen PØ. Reply letter: Mental health of people who have used classical psychedelics and no other illicit drugs. J Psychopharmacol. 2015 Sep;29(9):1036-40. PubMed PMID: 26649373. 

10: Krebs TS, Johansen PØ. Over 30 million psychedelic users in the United States. F1000Res. 2013 Mar 28;2:98. doi: 10.12688/f1000research.2-98.v1. eCollection 2013. PubMed PMID: 24627778; PubMed Central PMCID: PMC3917651.

11: Logan BK, Goldfogel G, Hamilton R, Kuhlman J. Five deaths resulting from abuse of dextromethorphan sold over the internet. J Anal Toxicol. 2009 Mar;33(2):99-103. PubMed PMID: 19239735.

12: Larsen JK. Neurotoxicity and LSD treatment: a follow-up study of 151 patients in Denmark. Hist Psychiatry. 2016 Jun;27(2):172-89. doi: 10.1177/0957154X16629902. Epub 2016 Mar 10. PubMed PMID: 26966135.

13:  Lee MA, Shlain B.  The Complete Social History of LSD: The CIA, The Sixties, and Beyond.  Grove Press, New York, 1985: p 294.

14: Mithoefer MC, Grob CS, Brewerton TD.  Novel psychopharmacological therapies for psychiatric disorders: psilocybin and MDMA. Lancet Psychiatry. 2016 May;3(5):481-8. doi: 10.1016/S2215-0366(15)00576-3. Epub 2016 Apr 5. Review. PubMed PMID: 27067625.

15: Johnson M, Richards W, Griffiths R. Human hallucinogen research: guidelines for safety. J Psychopharmacol. 2008 Aug;22(6):603-20. doi: 10.1177/0269881108093587. Epub 2008 Jul 1. Review. PubMed PMID: 18593734.

Attribution:

1:  Krebs TS and Johansen PØ. Over 30 million psychedelic users in the United States [version 1; referees: 2 approved]. F1000Research 2013, 2:98 (doi: 10.12688/f1000research.2-98.v1)

Copyright: © 2013 Krebs TS and Johansen PØ. This is an open access article distributed under the terms of theCreative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

2:  Figures 2 and 5 are from Substance Abuse and Mental Health Services Administration (SAMHSA) Emergency Department Data.

Epidemiology and Toxicology of Aircraft Assisted Pilot Suicides

I thought I would add a few facts to the speculation about what is really known about the epidemiology and toxicology involved in aircraft assisted suicides. It turns out that there are substantial studies that have been written.  If you are a bottom-line kind of person and want to avoid further reading, I can tell you that the events are rare especially events involving commercial aircraft where the incident is ruled a suicide by aviation authorities.  The events are so rare that prediction is doubtful.  In many cases the descriptions of suicidal statements and behavior occur on the day of the events and there are further extenuating circumstances like the use of alcohol and other intoxicants.  If you are really interested in these events, there are numerous places where you can see the analysis of what happened and what the ruling was by the National Transportation Safety Board (NTSB). 

The media reaction is similar to what is seen following mass shootings in the United States.  After the initial shock, there is typically a period of speculation about the causes of the disaster of the form: “What motivates a person to do something like this?”  There is the invariable dissection of their life in the media.  Were they bullied?  What was their personality like? What was on their computer?  Were there any clues that were missed that suggested that one day they would start shooting people?  Were psychiatrists involved?  How did they get the firearms?  When all of those familiar touchstones are exhausted (and it does not take long), the analysis starts to take on the characteristics of groups with agendas.  Gun advocates will suggest that this person was not a typical gun owner and therefore tighter gun laws are not needed.  Gun control advocates will provide the counter arguments that usually involve how easy it was for this person to get a gun.  There is a political impasse largely due to the power of the gun lobby and some politicians start to talk about “being in the wrong place at the wrong time.”  Mental health advocates, especially anyone who wants to talk about the real problems of mental illness and violence are as disenfranchised as the gun control advocates.  Nothing ever happens.  The screening advocates step up and suggest that many of these incidents could be prevented if we just “screened” enough people.  Anyone familiar with Bayesian statistics knows why that won’t work and may cause more harm than good. 

After that impasse, a second wave of speculation starts driven largely by people who ascribe to the theory that psychiatric medications and psychiatric treatment can cause homicidal behavior.  There are a couple of schools of thought on that one.  The first has to do with medications and the idea that specific medications like SSRIs can lead to homicidal behavior.  The other has to do with the fact that seeing a psychiatrist is associated with homicidal behavior and therefore psychiatric treatment must at some level cause homicidal behavior or at the very least the psychiatrist is responsible for not stopping it.  As I explored in a previous posts – there is not a shred of evidence that any of that is true.  There is however more evidence about pilot safety, pilot use of antidepressants, and incidents ruled pilot suicide than I have seen discussed in the media.  Here are a few bits of solid data to ponder during the expected swell of speculation about causes, who is to blame, and possible solutions.

1.  The denominator is huge:  

When the FAA or NTSB looks at all certified pilots in the US that includes a total of roughly 620,000 people per year including classifications for student, recreational, sport, private and commercial.  Roughly 1/3 of the FAA certified pilots are classified as commercial.  The US government also collects detailed statistics on the total number of passengers flown per year (815.3 million), the total number of flights per year (9.821 million) and a host of associated statistics on the Bureau of Transportation Statistics web site. 

2.  The numerator is very small:  

A quick glance at the table below on either antidepressant use by pilots or the total incidents rules as suicide shows that a small proportion of the total deaths are associated with either suicide or antidepressant use.  The proportions of the total pilots in the data base is much smaller and the rates of both suicide and antidepressant use are much lower than expected on a population wide basis.  Data from the Aviation Safety Network suggests that there were 8 to 10 incidents involving commercial aircraft and pilots since 1976 or about 9 in the last 40 years.

3.  The data on pilot use of antidepressants in fatal crashes: 

 Until about 2006, the FAA prohibited the use of antidepressants by commercial pilots.  They have since modified their stance to allow for specific antidepressants.  The European Aviation Safety Administration has publicly posted information of the safety of pilots and necessary screening for psychiatric disorders as well as prohibitions on certain diagnoses.  There have been studies that look at positive toxicology for antidepressants in the cases of fatally injured pilots.  These studies have looked for the presence of tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) in in fatal crashes.  Tricyclic antidepressants were the predominant antidepressants prescribed before the approval and release of fluoxetine in 1987.  One study by Dulkadir, et al looked at fatal crashes between 1990 and 2012.  In this study the researchers received biological samples from 7,037 fatally injured pilots out of a total of 8,429 fatal accidents.  2,664 were positive for drugs on toxicological analysis.  Of those positive samples TCAs were found in 31 samples, TCAs alone in 9 and TCAs with other drugs in 22.  None of the pilots involved reported TCA use during their aviation medical exam.  The authors point out that at the time covered in this study that TCAs were not approved for pilot use and that selective serotonin reuptake inhibitor antidepressants or SSRIs were approved on a case by case basis.  That is a prevalence of TCA use in this database is less than 0.5% ( 31/7,037 aviators).  That number is much lower than estimates of population wide use of antidepressants.

Where the blood levels were determined they clearly indicate that some overdoses had occurred (see Table II and III).  Blood concentrations greater that 1,000 ng/ml are usually very consistent with overdoses and that is the case with nortriptyline and imipramine/desipramine in these tables.  The authors were able to determine that the TCAs were prescribed for depression in three cases, pain in two cases, and chronic insomnia in one case.  Other antidepressants were listed along with opioids, anticonvulsants, cold medications, antihypertensives, benzodiazepines, muscle relaxants, diabetes medications and ethanol were detected but the epidemiology was not reported.  In both the studies by Akin and Dulkadir “drugs and alcohol and/or a medical condition” was given as “a probable cause or contributing factor in about 1/3 of the accidents where antidepressants were detected.

There was an earlier study of the epidemiology of SSRIs in pilot fatalities from 1990-2001 (Akin, et al) that showed they were involved in 61/4,128 pilot fatalities or a total of 1.48%.

The available data suggests that pilot suicide by aircraft is very rare and much lower than the pilot suicide rate by all methods.  There is also a suggestion that the suicide rate in pilots has actually decreased.  Searching the NTSB database yielded 74 fatal accidents using the search term "suicide" dating back to 1966. 

Explanations given in the article for the fewer pilots taking TCAs was that they are more toxic and less preferred agents.  Certainly in the 1990s SSRIs were heavily promoted along with the medical treatment of depression.

4.  Intoxicants are found in toxicology specimens –

The study by Canfield, et al identified a greater percentage of specimens that were positive for cannabinoids (relative to antidepressants) and additional performance impairing drugs in 38% of the individuals who tested positive to cannabinoids.  They also looked at the mean THC concentration in the blood and concluded that during 1997-2001 it was 2.7 ng/ml and for 2002-2006 it was 7.2 ng/ml.  The rate of increase in THC levels over those years exceeded the increase in cannabis potency as reported by the National Institute of Drug Use (NIDA) over the same years (2.7 fold as opposed to 1.5 fold).  Some authors have concluded that THC levels between 2 and 5 ng/ml represent the lower and upper ranges of significant impairment from cannabis use on performance tests measuring driving skill (see Ramaekers, et al) in recreational cannabis users.

The study by Bills, et al looked at the toxicology in a cohort of 36 pilots who committed suicide by aircraft during a 21 year period from 1983 and 2003.  Each suicide case was matched against 2 randomly selected control accidents.  In this study, the pilot characteristics included positive toxicology for alcohol, prescription drugs, and illegal drugs in 24.3%, 21.6%, and 13.5% of cases respectively.  An exhaustive list of drugs found was not available in the paper.  The authors were also not able to compare the toxicology of the cases to controls because 84% of the controls survived and their toxicology was unknown.  

5.  The baseline rate of pilot suicide is low or is it? -

Bialik looked at the issue of workplace suicide, the data quality estimates for pilots in the US.  One of the key references was a paper by Tiesman, et al that looked at the issue of workers who suicide in the workplace.  It used databases from the CDC (National Occupational Mortality Surveillance (NOMS)) and  Bureau of Labor Statistics (Census of Fatal Occupational Injury (CFOI)).  The NOMS database has no granularity and does given intentional self harm as a search parameter.  Unfortunately only "transportation occupations"  can be searched grouped by age, race, and sex.  I did not find the number of deaths or the PMR (Proportionate Mortality Ratio) to be useful.  The NOMS did have granularity with specific occupations and there was a homicide definition but none for suicide or intentional self harm.  Bialik concludes that pilots in general may have a slightly higher rate of suicide than the population in general but there are problems with that estimate and he was able to consult with an epidemiologist from the CDC.

Another approach to looking at this issue to to find a study with a very well characterized database that looks at the occupational issue.   Roberts, et al meets that criterion in a 2013 study of high-risk occupations for suicide.  The researchers looked at the numbers of suicides and numbers in all occupations in England and Wales for specific time intervals.  They determined the 30 occupations with the highest suicide rates (generally greater than 20/100,000).  In comparing the time intervals (1979–80, 1982–83) to  (2001–2005) they determined shift in the ranking and discussed possible causes of those changes.  Pilots were not listed in the top 30 occupations by suicide rate.  The only transportation workers listed were "rail transport operating staff".  They noted that suicide rates for professional occupations decreased over the time interval studied while there were sharp increases in the suicide rates for manual occupations.  As a comparison the 2013 suicide rate in the US was 12.6 per 100,000.

6.   The accident rate due to suicide attempts in commercial aviation is lower than that found in general aviation - 

These incidents are tracked  by the Aviation Safety Network and their web site currently lists intentional incidents and accidents caused by pilots dating back to 1976 in commercial flights.   There is a separate list of aircraft accidents caused by pilot suicide and that lists 9 suicides in the same time period but proportionally more associated fatalities. 

7.  Pilots can already self report substance use problems - 

There have been some suggestions that screening would be enhanced if pilots could self report problems without the fear of recrimination - the same way that licensed health care professionals are allowed to do in many states.  The focus would be on treatment rather than punishment.  The health care professional experience demonstrates that this leads to significantly more self reports and that is consistent with the goal of public safety.  Since pilot certification occurs at the federal level and health care professional licensing occurs at the state level - there is an opportunity to develop a more standardized approach to the potentially compromised pilot that depends more on self-report than screening.  There is currently an "occupational substance abuse treatment program" called HIMS that states at least part of their goal is to preserve careers.  A broader focus to include voluntary self- report of psychiatric conditions and suicidal thinking would result in more referrals for treatment and potentially impact the suicide rate.

8.  Aviation regulators and the aviation industry collect data that the healthcare industry can only marvel at - 

Reading through the sheer amount of data and how it is acquired it is evident that anyone involved in aviation has a single-minded focus on safety.  The methods of data acquisition through flight recorders and the checks and balances on the ground are far superior to any safety standards in the health care industry in the United States.  As a basic thought experiment, can you imagine recording similar outcome data from patients rapidly discharged from hospitals in the US?  I am talking about real data and not the survey that the nurse hands a patient after they have coached them on what to check off. 

I don't have to imagine what that data would look like.  I know what that data looks like and it is quite ugly.  It is more than a little ironic that health care experts, especially in this case psychiatrists and other behavioral experts are going to rush in and correct what is wrong with the aviation industry.  By comparison, health care measurement and incident analysis is all smoke and mirrors.  They don't know how to collect relevant data and many of the outcome measures are strictly political and meaningless.  If anything we should be bringing in aviation safety experts to run hospitals instead of MBAs.

With what I have read, I doubt that there is any possible improvement beyond voluntary reporting and making sure that there is always a second crew member in the cabin on commercial airliners.  In some of the commercial aircraft crashes the planes were stolen by staff who were not pilots and crashed.  But in the case of air disasters that resulted in multiple passenger deaths a second person in the cabin is a clear safeguard.  I am not an expert on how many people are in air crews, but I know that there is also a flight engineer in the cabin in some cases.  Given that these incidents are rare by any combination of numerators and denominators that are chosen and the fact that screening for rare events is generally not successful, screening for these rare events is not likely to work.  Flight crews currently undergo random urine toxicology to prevent the use of intoxicants that can impair the ability of a pilot.  Anecdotal evidence would suggest that is useful, but in the case of addictions there are often attempts to circumvent this intervention or use a drug that is not detectable.  The experience of health care professional screening programs would suggest that voluntary reporting can both improve public safety and preserve careers.  That seems like a useful approach for pilots.

Most importantly, the aviation industry is a model for safety assurance and the investigation of incidents where there were lapses.  It holds many lessons for the health care industry.        




George Dawson, MD, DFAPA



Akin A, Chaturvedi AK. Selective serotonin reuptake inhibitors in pilot fatalities of civil aviation accidents, 1990-2001. Aviat Space Environ Med 2003; 74(11):1169–76

Canfield DV, Dubowski KM, Whinnery JE, Lewis RJ, Ritter RM, Rogers PB.  Increased cannabinoids concentrations found in specimens from fatal aviation accidents between 1997 and 2006. Forensic Sci Int. 2010 Apr 15;197(1-3):85-8. doi: 10.1016/j.forsciint.2009.12.060. Epub 2010 Jan 13. PubMed PMID: 20074884.

Zeki Dulkadir,  Gülhane, Arvind K. Chaturvedi, Kristi J. Craft, Jeffery S. Hickerson, Kacey D. Cliburn. Antidepressants Found in Pilots Fatally Injured in Civil Aviation Accidents.  Federal Aviation Administration, Office of Aerospace Medicine, Nov 2014.

Lewis RJ, Johnson RD, Whinnery JE, Forster EM. Aircraft-assisted pilot suicides in the United States, 1993-2002. Arch Suicide Res. 2007;11(2):149-61. PubMed PMID: 17453693.

Russell J. Lewis, Estrella M. Forster, James E. Whinnery, Nicholas L.  Webster.  Aircraft-Assisted Pilot Suicides in the United States, 2003-2012  Civil Aerospace Medical InstituteFederal Aviation Administration. Oklahoma City, OK 73125 February 2014

Ungs TJ. Suicide by use of aircraft in the United States, 1979-1989. Aviat Space Environ Med. 1994 Oct;65(10 Pt 1):953-6. PubMed PMID: 7832739.

Bills CB, Grabowski JG, Li G.  Suicide by aircraft: a comparative analysis.  Aviat Space Environ Med. 2005 Aug;76(8):715-9. PubMed PMID: 16110685.

Ramaekers JG, Moeller MR, van Ruitenbeek P, Theunissen EL, Schneider E, Kauert G. Cognition and motor control as a function of Delta9-THC concentration in serum and oral fluid: limits of impairment. Drug Alcohol Depend. 2006 Nov 8;85(2):114-22. Epub 2006 May 24. PubMed PMID: 16723194.

Roberts SE, Jaremin B, Lloyd K. High-risk occupations for suicide. Psychol Med. 2013 Jun;43(6):1231-40. doi: 10.1017/S0033291712002024. Epub 2012 Oct 26. PubMed PMID: 23098158; PubMed Central PMCID: PMC3642721.

Total FAA Certified Pilots:  http://www.aopa.org/About-AOPA/General-Aviation-Statistics/FAA-Certificated-Pilots

Aviation x Antidepressant Medline Search April 2015:  http://www.ncbi.nlm.nih.gov/sites/myncbi/1-MAvBcofi/collections/47791909/public/

Carl Bialik. We Don't Know How Often Pilots Commit Suicide.  FiveThirtyEight (a very sophisticated blog)

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