Medical Treatment Is Never A Zero Risk Decision

Harvey W. Cushing, MD

Ever since Medical Errors - the Third Leading Cause Of Death came out the media and bloggers have been abuzz with the headline.  It is only a matter of time before we hear about how many full 747s crashing would equal the number of patients that are killed by physician errors each year.  There are any number of articles in the press each day about how there are algorithms or checklists from some committee or government agency that will eliminate risk in medical diagnosis and procedures.  There are an equal number of stories about how machine intelligence or will eliminate all of this human error.  There was a story a few weeks ago about a robot that could suture up operative wounds from surgery.  After seeing that robot in action, I would not want it anywhere near me or anyone I cared about.  There is often palpable conflict of interest involved in the news stories.  Stories designed to generate interest or influence politicians.  Stories to express a political viewpoint.  Even in the professional literature, much of what is written is a political viewpoint often to develop leverage against physicians and force them to do things in a certain way.  The selling point to the public and their elected officials is that medicine, particularly physicians would perform better and more uniformly if they would adhere to certain protocols and that these protocols need to include the input of people who have never been trained as physicians - most notably business managers.          

I can illustrate why these analyses are absurd based on an experience I had about 6 years ago.  At that time my wife was struggling with intense ear pain and the provider she was seeing wanted to start her on another course of antibiotics for ear pain.  I had her see an ENT surgeon instead, who performed an examination that only an ENT physician can do and then read the CT scan that he ordered.  That CT scan was read as normal by the radiologist.  This ENT physician not only read it as abnormal, but got additional imaging studies to demonstrate that my wife had a pituitary tumor.  Referral to an endocrinologist confirmed that it was a growth hormone secreting tumor, further explaining additional symptoms that she had described to various physicians over the years.  I went to work at that point and found the neurosurgeon who was one of the pioneers in transsphenoidal adenoma resections in the world.  Although not malignant, the prognosis of these tumors is not benign with disfigurement from acromegaly, progressive endocrine abnormalities, and eventual congestive heart failure all from the effects of excessive growth hormone secretion.  There were also complications of inadequate excision and secondary procedures like gamma knife irradiation in an attempt to obliterate the tumor.  We were sitting in the consulting room of the neurosurgeon as soon as we could arrange it.

He had pulled up a coronal section of the MRI scan showing the tumor wrapped around my wife's right internal carotid artery.  He made the following statement:  "This is the tumor and this is the artery (pointing to areas on an MRI coronal view of the pituitary gland and surrounding anatomy).  I am going to try to remove as much of the tumor as possible.  If I accidentally nick the carotid artery in this area, there is nothing that can be done about it.  That complication happens and I know good neurosurgeons who have had that happen to them.  I can assure you I will remove only as much tumor as possible.  I will remove only as much as I would remove if you were one of my family members."

This is the unspoken truth about medical errors and whether they are preventable or not.  In this case doing nothing results in an inevitable slow death and severely compromised quality of life.  The procedure is not without risk.  In this case the risk was minimized by selecting the most skilled neurosurgeon in the area, but he openly acknowledges that nicking the carotid artery in a place that cannot be repaired is not only a possibility, but it happens to the best neurosurgeons.  Any cursory analysis should illustrate why.  We are talking about an operation that occurs in about a 1 1/2 inch space at the tip of an endoscope on a tumor that extends away from that tip into a small crevice between the carotid artery and sphenoid bone.  Anyone really interested in this can go to YouTube and view several videos of the procedure from the view of the surgeon.  In this case our neurosurgeon explicitly talked about the issue of how much tumor could be removed.  He was acutely aware that the risk involved in removing too much tumor may be unacceptably high.  Incompletely removing the tumor involves the risk of continued exposure to excessive growth hormone and the secondary gamma knife procedure.     The fact that this surgery can be done at all seems like is a miracle to me.  Early in my  career, I had treated a patient who underwent a transtemporal approach to the same kind of tumor and that had resulted in significant postoperative disability.
                                                               
In the decision to proceed my wife clearly found the risk acceptable because acromegaly and a slow death from endocrine complications and further procedures were not.  The operative procedure went perfectly and 6 years later her growth hormone, IGH levels, and serial MRI scans show no tumor recurrence.  I don't have to speculate about what might have gone wrong in my wife's case because Henry Marsh (6) writes about it in his compilation of neurosurgical complications Do No Harm.  In the chapter "Pituitary Adenoma" he did a transphenoidal procedure on a man with acromegaly.  His description of the relevant anatomy: "There are however, two major arteries next to the pituitary gland that can, if the surgeon is exceptionally unlucky, be damaged during the operation."  His patient did well until post-operative day number 3, when suddenly his right arm was paralyzed and he could not communicate.  Brain imaging confirmed a major left hemispheric stroke.  Having no actual operative complications Marsh concludes: "This must have been caused in some unknowable way by the operation."

But let's take a look at what would have happened in my wife's case if there had been a complication or series of complications using the methodology cited by the authors in the studies.  First off, in the case of a complication where does the chain of errors begin.  The misdiagnosis of otitis media and two antibiotic prescriptions?  The misread CT scan of the sphenoid bone?  It seems like those are two preliminary errors right there even though neither was immediately threatening.  Combined with a surgical error that would be three medical errors had a complication occurred.  And what about the self correcting aspects of this process?  Does the ENT surgeon get any credit here for correcting the misdiagnosis of otitis media or the misreading of the CT scan?  Any focus on medical errors never looks at the self correcting aspects - how many times they are caught and how many times standard second opinions from colleagues or trusted referrals modify the treatment plan.  How much morbidity and mortality would occur without this level of self correction?  How is it estimated?  The best example I can recall of the problems of error determination was in a NEJM editorial to address the first report on medical errors by the Institute of Medicine.

In that editorial (5), the lead author of some of the most quoted studies discusses the issue of the definition of errors, the definition of preventability, and the subjective nature of these determinations.  His preliminary analysis is that the IOM conclusion that 44,000 to 98,000 deaths caused by medical errors "create an impression that is not warranted by the scientific work underlying the IOM report."  That number has been inflated to more than 250,000 according to the recent quoted report (1).   He also expresses an opinion completely consistent with Marsh's observations and goes on to point out that the observation of error can not cannot be reliably made by third party observers:

"Even with the best surgical technique and proper precautions, however, a hemorrhage can occur. We classified most postoperative hemorrhages resulting in the transfer of patients back to the operating room after simple procedures (such as hysterectomy or appendectomy) as preventable, even though in most cases there was no apparent blunder or slip-up by the surgeon. The IOM report refers to these cases as medical errors, which to some observers may seem inappropriate." (6)

He goes on to elaborate on four important aspects of the IOM report, 2 of which have to do with politics and public perception.  The first is the idea that either nothing is being done about safety or that things are getting more dangerous.  In many ways this is analogous to the public perception that violent crime is high when it is at a 30 year low.  He gives an even better example of Harvey Cushing's accomplishments during his neurosurgical career.  In 1913, the mortality rate for craniotomies for brain tumors was 80%.  In twenty years it was reduced to 13%.  Currently it is 1%.  All of that without the IOM or any of the current federal or state regulators.  The whole idea that physicians are motivated more by adhering to what politicians or regulators want rather than what is in the best interest of their patients has always been an incredible one to me.  I guess it makes sense only if you are a politician or a regulator and you really believe that your naively designed incentives and disincentives have meaning.   The second complication is increased reporting requirements and all of the complications that involves including the impact on confidential peer reviewed complications.  Every physician has participated in some form of complications conferences or what surgeons used to call morbidity and mortality conferences.  The modern goal of these conferences is to try to identify procedures and interventions to improve patients safety.  Opening that system up to increased reporting and subjecting it to the "dead weight of the litigation system" is something the author cautions against, but is often explicit in the news headlines.

Makary thought the IOM missed the boat on the issue of how malpractice litigation is a risk against internally driven safety initiatives.  I think they and subsequent authors missed the boat on the issue of biological variability.  To some degree is it addressed by the subjective determination of preventability but not entirely.  If a neurosurgeon is observed to have performed an errorless operation and the patient sustains significant complications, what are all of the factors that go into calling that an error or not?  A lot of it may have to due  with the baseline state of the patient.  Are they already compromised by injury, illness or congenital variations.  Neurosurgeons after all are not operating on healthy people.  The example also applies to medicine and psychiatry.  As an example, I usually tell people up front these days that there is about a 40% chance that they will noticeably improve with an antidepressant if their symptoms are significant.  There is another 20 or 30% chance that they will feel somewhat better but not get back to their baseline state.  There is a 10-20% chance that they will get significant side  effects and not want to continue the medication and in a small number of cases (1-2%) there is a chance of really severe side effects from the medication.  Pharmacogenomics suggests that it can be invaluable in this process, but there is variability between predictions using the available analyses from the same manufacturer and between manufacturers.  Even with that warning there are a number of people who will consider it an "error" that they received a medication that caused them to get a rash or in the worst case serotonin syndrome.  I think that there is a natural tendency for some to see any medical procedure that does not go well to be attributable to error on the part of the physician.  I think that the personal experience of most physicians will bear that out.        

Another less well known intervention in psychiatry is the care of the chronically suicidal person.  Many of these persons have a history of serious suicide attempts and remain at significant risk.  The usual risk factor analysis of their suicide potential does not add very much.  There are frequently inadequate resources to treat them or they refuse to access what is available.  Frequent short term admissions to inpatient units adds nothing to their care.  The psychiatrist who accepts their care usually is seeing them more intensely and accepting more crisis calls from them than other patients.  Until a sufficient therapeutic alliance develops, there may be many sessions with a lot of depression and anger and very little objective information on what the patient is thinking.  The psychiatrist and patient in this case need to accept that the risk involved in this situation from suicide or a suicide attempt - is necessary to make progress and enhance the patient's ability to function and enjoy life.

My main point here is that people currently need to assume some risks in order to get better.  There is nobody more than physicians who would want medicine to be a no risk endeavor, but the reality is that is not going to happen anytime soon.   All patients realize this at some level, but that may do little to mitigate the anger or disappointment when it occurs.  Every family has a tale to tell about a medical miracle or a medical mistake.   In the situations like my wife faced with my support, people are clearly willing to take the risk in face of undesirable consequences.  The physicians involved see this as very serious work.  Should the classification of medical errors be refined and analyzed?  Of course they should - but the approach being used in the press invoking planes full of patients being sent to their death by physicians being equated to terrorists is not accurate or helpful.  The backlash is significant and impairs the ongoing error analysis and correction process.  Equating a heterogenous collection of complications classified by different methods as errors and listing them as a standard cause of death is also not accurate or helpful to the science of medical error analysis and correction.


George Dawson, MD, DFAPA


References:

1:   Makary MA, Daniel M. Medical error-the third leading cause of death in the US. BMJ. 2016 May 3;353:i2139. doi: 10.1136/bmj.i2139. PubMed PMID: 27143499.

2: Brennan TA, Leape LL, Laird NM, Hebert L, Localio AR, Lawthers AG, Newhouse JP, Weiler PC, Hiatt HH. Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. N Engl J Med. 1991 Feb 7;324(6):370-6. PubMed PMID: 1987460.

3: Leape LL, Brennan TA, Laird N, Lawthers AG, Localio AR, Barnes BA, Hebert L, Newhouse JP, Weiler PC, Hiatt H. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. N Engl J Med. 1991 Feb 7;324(6):377-84. PubMed PMID: 1824793. 

4: Localio AR, Lawthers AG, Brennan TA, Laird NM, Hebert LE, Peterson LM, Newhouse JP, Weiler PC, Hiatt HH. Relation between malpractice claims and adverse events due to negligence. Results of the Harvard Medical Practice Study III. N Engl J Med. 1991 Jul 25;325(4):245-51. PubMed PMID: 2057025. 

5: Brennan TA. The Institute of Medicine report on medical errors--could it do harm? N Engl J Med. 2000 Apr 13;342(15):1123-5. PubMed PMID: 10760315.

6:  Marsh H.  Do No Harm: Stories Of Life, Death, And Brain Surgery.  Thomas Dunne Books/ St. Martin's Press; New York,  NY; 2014.


Attribution:

Portrait of Harvey Cushing, MD by Edmund C. Tarbell [Public domain], via Wikimedia Commons at https://commons.wikimedia.org/wiki/File%3ADr_Harvey_Cushing_Edmund_Tarbell_1908.jpeg accessed on May 22, 2016.


Supplementaries:

Supplementary 1:  Another excellent example of biological variability is joint replacement surgery.  I see patients, friends and family members who have mixed experiences.  The majority turn out very well, in some cases extremely well.  In the case of extremely good joint replacement surgery, according to all of these people I talk to, the surgeon seems to discourage them talking to other people about how good the results were, generally by telling them that they had an extraordinary result in terms of how the replaced joint functions.

Supplementary 2:  A good example from a recent post about the aggressive treatment of pain and the risk of addiction and overdose deaths.  20 years ago when physicians were being criticized by various factions for not aggressive enough use of painkiller prescriptions and the use of opioids for chronic noncancer pain - the risk of death by overdose was minimized by those proponents.  Now that there is a clear cause of death from overuse of opioids and the rates of addiction have increased - physicians are faulted for not knowing how to prescribe opioids.  It seems like they had a better idea 20 years ago before yielding to the critics.  From the perspective of this post - there is always risk either way.  Only politicians and regulators can deny that.

Supplementary 3:  The Twitter graphic ( and yes I am serious).  The IOM did not start until about 1970.  None of these entities has a track record remotely close to Harvey Cushing in the 1920s and 1930s.

           

The NY Times Opinion On Congress and the Opioid Epidemic

The NY Times came out with an opinion piece of the opioid epidemic on May 16 (1).  In their opinion it was a good thing that Congress had finally decided to "get involved."  They emphasize the need to fund treatment and prevention programs.  But wait a minute, didn't Congress already approve the The Paul Wellstone and Pete Domenici Mental Health Parity and Addiction Equity Act of 2008 (MHPAEA).  That act was supposed to provide equal treatment for mental disorders and addictive disorders.  Here it is a few years later and we are supposed to be still trying to fund treatment despite a specific piece of legislation was was already supposed to provide funding?  In fact, this same editorial board came out with a very rosy assessment of the MHPAEA three years ago and they were wrong back then as well.  In that link, I posted reasons why the parity act would fail and of course - it did.  That failure is the only reason the editorial board is now calling for funding for treatment and prevention programs,  I criticized their original post because they lacked anyone with medical expertise on their panel and they did not seem to know how health care works or why Congressional intervention does not work. It looks like the same mistake has been repeated.  At some point we need to recognize that the opinions and legislation about health care aren't worth the paper they are printed on.  At least from the perspective of the prospective patient or the physicians who are trying to treat them.

This piece does reflect a dim grasp of the health care system in this country that is set up by Congress in the first place.  Some of the suggestions made me want to laugh out loud.

"The federal government can make the biggest difference by expanding high-quality treatment programs. States, which have more sway over doctors and hospitals, need to do more on the prevention side by placing limits on opioid prescriptions. States can encourage doctors to order alternative pain treatments, like physical therapy, and require insurers to cover those services." (1)

This seems to assume that the federal government is somehow interested in quality while they are setting up managed care organizations that really have nothing to do with quality.  Everything is set up to be cost-effective (translation = cheap).  There is nothing cheaper in the way of mental health care and treatment for addictions than refusing to fund it and that is a routine occurrence in spite of the MHPAEA, the bill that was supposed to put the care of mental illnesses and addictions on par with other medical conditions.  The second error in this paragraph is the idea of a bureaucrat somewhere placing limits on opioid prescriptions.  That will immediately alienate the majority of the physician workforce that currently prescribes opioids appropriately and of course the patients of these physicians.  And finally the idea that alternate treatments will be covered misses the cultural contributions to the opioid epidemic and the fact that Congress doesn't seem to be able to mandate insurance companies to do much of anything.  If they can't mandate equal coverage for mental illness and addiction, why would physical therapy be any different?

On the question of how much legislation must be written and how much money appropriated, the money figures quoted range from $600 million to $1.1 billion to address the treatment needs of 435,000 regular heroin users, 1.9 million people who are regular prescription opioid users, and 4.3 million people engaged in non-medical use of prescription painkillers each month.  Considering only the prescription of buprenorphine for medication assisted treatment of opioid use disorder and the $1.1 billion dollar figure, at about $1,000/month for buprenorphine, that figure would result in the treatment of 92,000 individuals and that is not including the cost of medical evaluation and administration of the drug.  That is less than a quarter of the heroin users and less than 10% of the painkiller users.  It also does not fund any of the additional treatment services including addiction counseling and a continuum of sober support and housing.

In situations like this, seeming to address the problem by political one upmanship is always tempting.  A Governor is quoted in the article giving her opinion that the cause of the current epidemic is the prescribing practices of physicians.  I am sure that many legislators take the same concrete approach to problems but this is a much more nuanced problem.  Technically speaking - all physicians leave medical school knowing how to prescribe opioids.  Not all of them are good at managing the relationship with the patient or telling patients what they might not want to hear.  The commonest errors I see in prescribing addictive drugs to people has nothing to do with technical expertise of the physician.  It has to do with the idea that the patient is in distress and that it is the physician's job to do something about it.  Many of these physicians have a difficult time balancing the decision to prescribe an addictive drug versus the potential harm of addiction or the harm of not treating a pain syndrome that does not respond well to opioids.  Many of these same physicians lack an understanding of addiction and the fact that it is possible to continue to take an addictive medication even though it is providing no symptomatic relief from pain.   The third problem is the patient's lack of insight.  There a lot of biases when it comes to addiction and assigning responsibility.  There are numerous arguments about whether addiction is a disease or not and these are generally arguments about who is responsible for the addiction and its treatment.  I don't think that there is any doubt that a person who is addicted to opioids will behave in a predictable manner to keep the addiction going.  They will not tell their physicians that they have an addiction and in some cases try to get extensions on prescriptions, escalate the dose of a prescription, get more opioids from non-medical sources (dealers or acquaintances) or use the opioid for a reason that it was not intended - usually insomnia, anxiety, or depression.  How do legislators address this complex problem?  Basically by blaming physicians and passing legislation that doesn't make any sense.

It is important to remember that this epidemic did not start in a vacuum.  There was an activist movement among some professional societies and regulatory bodies to treat pain more aggressively.  Looking at past  New York Times editorials, some of this was recorded and in at least one case, the opinion came down on the side of aggressive pain treatment.   Congress and the media seems to have come full circle on the issue of opioids and is ready to head back in the other direction.  The news can be a powerful source of influence in encouraging people to use public health measures to stop this epidemic.  That can be as basic an idea as not hoarding leftover opioid painkillers and discarding them.

Hoping that Congress will solve the problem, when they were supposed to 7 and 22 years ago, does not seem like the best idea.  If they went back to sleep - nobody would notice the difference.


George Dawson, MD, DFAPA



1:  The Editorial Board.  Congress Wakes Up To The Opioid Epidemic.  New York Times May 16. 2016.

2:  The Editorial Board.  Making the Pain Go Away.  New York Times.  March 4, 1994:

"The new guidelines, issued in detail for physicians and in brief for patients, call for treating pain early and aggressively, starting with the simplest options, like aspirin and acetaminophen, and progressing through mild opiates to more potent drugs like morphine."

And....

"But there are scant data from scientific studies to document whether or not marijuana is as effective as or better than other anti-nausea drugs. The same outdated attitudes that inhibit the use of narcotics for pain relief should not be allowed to suppress clinical investigations into the therapeutic uses of pot."

Pimavanserin

Pimavanserin

The first time I heard any details about this compound was in a course for movement disorder specialists.  I have been a long time member of the Movement Disorder Society and get their journal Movement Disorders.  From time to  time, a mildly recurrent theme has been antipsychotic agents that can be used in specific movement disorders that do not worsen the underlying problem primarily by their activity at the dopamine-2 (D2) receptor.  One of the research interests in atypical antipsychotics over the past 20 years has been to look for this property.  In studying atypical antipsychotics in  Parkinson's patients, it  turns out that only one of these drugs does not worsen Parkinson's and that is clozapine.  There are several target populations that a drug with no liability to worsen dopamine (DA) mediated movement disorders would be useful.  The first is patients who require antipsychotic medications for bipolar disorder or schizophrenia and develop Parkinson's disease or tardive syndromes from typical or atypical antipsychotic medications.  The second group is patients with Parkinson's disease who develop psychotic symptoms associated with the primary neurological illness.  Both groups are significantly represented in geriatric psychiatry practices and despite the widespread availability of atypical antipsychotics medications in the last 20 years, geriatric patients with bipolar disorder or schizophrenia and severe movement disorders - usually tardive syndromes still exist.  A medication that does not affect the DA mediated locomotion system is potentially of great benefit.

In the conference I attended, there was an entire lecture devoted to the Non-Motor Features of Parkinson's Disease.  Results from the Sydney Multicenter Study were presented.  The study followed a cohort of Parkinson's survivors for 15 and 20 years and discovered that by year 15 - 85% had cognitive decline and 50% were depressed.  By year 20 - 56% had hallucinations, 50% were on antidepressants, and 75% had dementia by the time of death.  Delusions occur but at a much lower rate.  The first step in treatment is to eliminate reversible causes including polypharmacy with anticholinergic and dopaminergic agents.  The treatment of moderate to advanced Parkinson's is by definition one that requires multiple medications.  Clozapine and quetiapine in low doses were suggested as the best direct treatments currently available.  At that time pimavanserin was discussed as a drug in Phase 3 trials.  It was presented as a serotonin (5-HT2A) inverse agonist with no activity at dopaminergic, adrenergic, histaminergic, and cholinergic receptors.  An abstract from ClinicalTrials.gov was shown of a study of 199 patients with Parkinson's Disease psychosis (PDP).  The primary outcome measure was a psychosis score on the Scale For Assessment Of Positive Symptoms adapted for Parkinson's (SAPS-PD).  Rarely used, qualitative, outcome measures are one of many limitations of geriatric studies.  On that measure, there was a more significant decrease in psychosis scores in the treated group.  The medication was fairly well tolerated with 10/95 subjects discontinuing it due to side effects compared to 2/90 in the placebo group.  No motor side effects were noted and there were no other safety concerns.  As noted in the supplementary sections there appears to be very little published data supporting the FDA decision to approve this drug in the marketplace.  It has been used to treat psychotic disorders but apparently only as an augmenting agent for antipsychotic medications and the preliminary study suggests it may work for augmenting an atypical medication like risperidone but not a typical agent like haloperidol.

There is data on file with the FDA indicating that a substantial amount of research is not published at this time.  The 173 page briefing materials for the Psychopharmacological Drugs Advisory Committee discusses the results of studies involving 1200 subjects receiving pimavanserin including 616 PDP subjects.  One of the interesting aspects of this document is that it includes the full text of the 20 - item Scale for Assessment of Positive Symptoms (SAPS) by Andreasen at the very end.  The SAPS-PD is a 9 - item modification that focuses on hallucinations and delusions.  Each of the 9 items is rated on the basis of increasing frequency with a maximum score of 5 indicating frequent daily occurrences.  The evidence footprint so far suggests the usual profile of a medication approved on a priority basis by the FDA.  The most important data - how it fares in clinical practice remains to be seen.  At this point it does not seem to be a first line or even second line drug for purely psychiatric applications and will probably be limited to PDP.

The pharmacodynamics of the drug are very interesting relative to all other available antipsychotic drugs.  The following table is from the briefing materials.

From Reference 1

The receptor affinities shown in the above table, indicate a unique profile for pimavanserin with essentially no affinities at histaminergic, muscarinic cholinergic, dopaminergic, and adrenergic receptors.  There are only two other antipsychotics with no activity in one class of receptors and in this case it has no affinity for four classes.  In theory this will eliminate a lot of side effects and the lack of dopaminergic activity should not lead to worsening Parkinson's Disease in those patients.

The other interesting aspect of the description of this compound as an inverse agonist.  Inverse agonists bind to the same sites as agonists but it has negative activity or efficacy at the site.  Antagonists have no intrinsic activity at receptors - they block the effects of agonists.  There are a significant number of inverse agonists in clinical practice and a number in current development or under study.

Reading through references 1 and 2 suggest that main safety concern is prolonged QTc interval at higher than recommended doses.  That lead to recommendations to avoid use with other QTc prolonging drugs.  In the older adult with Parkinson's who may also be already on an antidepressant and an antipsychotic and have pre-existing cardiovascular disease, the usual clinical approach with baseline ECGs and in some cases serial ECGs may be required.  From a pharmacokinetic standpoint, drug-drug interactions based on CYP3A4 inhibition or induction can lead to accumulation or clearance of the drug in the expected direction.

In thinking about prescribing pimavanserin, if I was working in the Geriatric Psychiatry and Memory Disorders Clinic where I worked for over a decade I would be looking forward to it.  There are many PDP patients and patients with tardive syndromes that do not tolerate typical or atypical antipsychotics alone.  In some cases, the symptoms are mild and do not require treatment, but in many cases they are persistent and totally disabling.  This medication may be an option for some of those patients.  As a member of two Pharmacy and Therapeutics Committee, this medication explodes the formulary myths of drugs in the same class being equivalent and therefore allowing for the least expensive drug to be used.  Inspection of the above table shows this is not really the case for other atypicals, but it is definitely not the case for pimavanserin.  Initially, I anticipate a steep prior authorization burden for any physician wanting to prescribe it even for the indicated condition and in this case it is:

NUPLAZID is an atypical antipsychotic indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease psychosis.

The critical question at this point is how it will work in clinical practice.  


 
George Dawson, MD, DFAPA



References:

1: Acadia Pharmaceuticals.  NUPLAZID™(pimavanserin); SPONSOR BACKGROUND INFORMATION FOR A MEETING OF THE PSYCHOPHARMACOLOGIC DRUGS ADVISORY COMMITTEE ON 29 MARCH 2016.

2: NUPLAZID™ (pimavanserin) package insert

3: Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases.  US patent: US 7659285 B2


Supplementary 1:  Current studies listed on ClinicalTrials.gov:


Study 1:

Title: A Study of the Safety and Efficacy of Pimavanserin in Patients With Alzheimer's Disease Psychosis
Recruitment: Recruiting
Study Results: No Results Available
Conditions: Alzheimer's Disease Psychosis
Interventions: Drug: Pimavanserin tartrate|Drug: Placebo
URL: https://ClinicalTrials.gov/show/NCT02035553

Study 2:

Title: A Study of the Safety and Efficacy of Pimavanserin in Patients With Parkinson's Disease Psychosis
Recruitment: Completed
Study Results: Has Results
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: pimavanserin tartrate|Drug: placebo
URL: https://ClinicalTrials.gov/show/NCT01174004

Study 3:

Title: A Study of the Safety and Efficacy of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis
Recruitment: Completed
Study Results: Has Results
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: Pimavanserin tartrate (ACP-103)|Drug: Pimavanserin tartrate (ACP-103)|Drug: Placebo
URL: https://ClinicalTrials.gov/show/NCT00477672

Study 4:

Title: Expanded Access of Pimavanserin for Patients With PD Psychosis
Recruitment: Available
Study Results: No Results Available
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: Pimavanserin tartrate
URL: https://ClinicalTrials.gov/show/NCT02762591

Study 5:

Title: A Study of Safety and Efficacy of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis
Recruitment: Completed
Study Results: Has Results
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: Pimavanserin tartrate (ACP-103)|Drug: Pimavanserin tartrate (ACP-103)|Drug: Pimavanserin tartrate (ACP-103)
URL: https://ClinicalTrials.gov/show/NCT00658567

Study 6:

Title: A Study of the Safety and Tolerability of Pimavanserin (ACP-103) in Patients With Parkinson's Disease Psychosis
Recruitment: Active, not recruiting
Study Results: No Results Available
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: pimavanserin tartrate (ACP-103)
URL: https://ClinicalTrials.gov/show/NCT00550238

Study 7:

Title: An Open-label Safety Study of Pimavanserin in Parkinson's Disease Patients
Recruitment: Completed
Study Results: No Results Available
Conditions: Parkinson's Disease Psychosis
Interventions: Drug: pimavanserin tartrate (ACP-103)
URL: https://ClinicalTrials.gov/show/NCT01518309

Study 8:

Title: Antipsychotic and Motor Effects of ACP-103 When Administered in Combination With Haloperidol and Risperidone
Recruitment: Completed
Study Results: No Results Available
Conditions: Schizophrenia
Interventions: Drug: ACP-103
URL: https://ClinicalTrials.gov/show/NCT00361166

Study 9:

Title: ACP-103 to Treat Parkinson's Disease
Recruitment: Completed
Study Results: No Results Available
Conditions: Parkinson's Disease|Dyskinesias
Interventions: Drug: Intravenous Levodopa|Drug: ACP-103
URL: https://ClinicalTrials.gov/show/NCT00086294

Study 10:

Title: Treatment of Hallucinosis/Psychosis in Parkinson's Disease by an Investigational Drug
Recruitment: Completed
Study Results: No Results Available
Conditions: Hallucinations|Psychoses|Parkinson's Disease
Interventions: Drug: ACP-103
URL: https://ClinicalTrials.gov/show/NCT00087542

Supplementary 2:  Published clinical trials of pimavanserin:

1: Cummings J, Isaacson S, Mills R, Williams H, Chi-Burris K, Corbett A, Dhall R,Ballard C. Pimavanserin for patients with Parkinson's disease psychosis: a randomised, placebo-controlled phase 3 trial. Lancet. 2014 Feb 8;383(9916):533-40. doi: 10.1016/S0140-6736(13)62106-6. Epub 2013 Nov 1. Erratum in: Lancet. 2014 Jul 5;384(9937):28. PubMed PMID: 24183563.

2: Meltzer HY, Elkis H, Vanover K, Weiner DM, van Kammen DP, Peters P, Hacksell U. Pimavanserin, a selective serotonin (5-HT)2A-inverse agonist, enhances the efficacy and safety of risperidone, 2mg/day, but does not enhance efficacy of haloperidol, 2mg/day: comparison with reference dose risperidone, 6mg/day. Schizophr Res. 2012 Nov;141(2-3):144-52. doi: 10.1016/j.schres.2012.07.029. Epub 2012 Sep 4. PubMed PMID: 22954754. 

 3: Ancoli-Israel S, Vanover KE, Weiner DM, Davis RE, van Kammen DP. Pimavanserin tartrate, a 5-HT(2A) receptor inverse agonist, increases slow wave sleep as measured by polysomnography in healthy adult volunteers. Sleep Med. 2011 Feb;12(2):134-41. doi: 10.1016/j.sleep.2010.10.004. Epub 2011 Jan 21. PubMed PMID: 21256805; PubMed Central PMCID: PMC3137254. 

 4: Meltzer HY, Mills R, Revell S, Williams H, Johnson A, Bahr D, Friedman JH. Pimavanserin, a serotonin(2A) receptor inverse agonist, for the treatment of parkinson's disease psychosis. Neuropsychopharmacology. 2010 Mar;35(4):881-92. doi: 10.1038/npp.2009.176. Epub 2009 Nov 11. PubMed PMID: 19907417.

5: Nordstrom AL, Mansson M, Jovanovic H, Karlsson P, Halldin C, Farde L, Vanover KE, Hacksell U, Brann MR, Davis RE, Weiner DM. PET analysis of the 5-HT2A receptor inverse agonist ACP-103 in human brain. Int J Neuropsychopharmacol. 2008 Mar;11(2):163-71. Epub 2007 Aug 21. PubMed PMID: 17708779. 

6: Vanover KE, Robbins-Weilert D, Wilbraham DG, Mant TG, van Kammen DP, Davis RE, Weiner DM. The effects of food on the pharmacokinetics of a formulated ACP-103 tablet in healthy volunteers. J Clin Pharmacol. 2007 Jul;47(7):915-9. Epub 2007 May 10. PubMed PMID: 17495279. 

7: Vanover KE, Robbins-Weilert D, Wilbraham DG, Mant TG, van Kammen DP, Davis RE, Weiner DM. Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers. J Clin Pharmacol. 2007 Jun;47(6):704-14. Epub 2007 May 1. PubMed PMID: 17473118.


Supplementary 3:

This is a blog so don't mistake my opinion for that of the FDA advisory committee or the package insert.  Read all package inserts like I do and let your patients know if you or anybody else is prescribing a medication for them that is off label.  I may discuss off-label uses, because I know it is going to happen and I am also discussing research applications that at this point are not even part of the FDA process.

News Flash From Channel 5: "There is a shortage of psychiatrists"

This was an actual headline from a local news channel.  Of course the first question is where have they been for the last 30 years?  That was about the last time Anoka Metro Regional Treatment Center (AMRTC) was adequately staffed by psychiatrists.  In fact, at that point some of the psychiatrists working there considered it to be a high point in the education of medical students from the University of Minnesota.  One of them told me that their clinical rotation was the highest rated of any in the department.  The gist of this story is that the shortage of psychiatrists has led to inconsistent staffing for patients who need consistency.  The reporter emphasis was on Minnesota Department of Human Services hiring three psychiatrists with disciplinary actions on record with the Board of Medical Practice.  They also make the point that many of their psychiatrists are flown in for a few weeks at a time to see patients and this disrupts continuity of care.  The mother of a patient and a State Ombudsman comment about the importance of continuity of care.  If you watch the entire clip, the end is rather anticlimactic as the reporter points out that Minnesota is really no different than other states.  They are all suffering from the shortage of psychiatrists.

All in all a very dramatic presentation of a problem that nobody wants to solve.  After all, I just pointed out that in the late 1980s and early 1990s staffing at this same hospital was excellent.  The psychiatric staff there was first rate and one of the best hospital staffs that could be found anywhere.  So what happened?   In a word that I have used frequently on this blog mismanagement.  At some point professional managers decided to ignore the once popular theories of Peter Drucker and manage professional workers like production workers.  They saw psychiatry as a production job and eliminated the systems aspects critical for a team approach to psychiatric treatment.  That team approach is also critical to the practice environment and the practice environment and patient care also suffers when governments and insurance companies start telling physicians what to do and what to prescribe.  The outcome is as predictable as the current failed state hospital system.

None of those basics are in this sensational piece from Channel 5 News.  The only narrative I can detect in this story is that there are long distance psychiatrists and problematic psychiatrists practicing problematic psychiatry at the state hospital - at least until the main reporter starts with a focus on the shortage of psychiatrists.  Psychiatrists in this story function only as scapegoats.  That is easy to do when you limit the practice and hire people who are willing to work in a compromised treatment environment.  It is also easy to do when you eliminate psychiatrists and experienced psychiatric nursing staff from the management and planning aspects of the system.   Just last week I pointed out that there were no psychiatrists on a Governor's Task Force on Mental Health.  There are no psychiatric experts discussing hospital care or what it will take to repair the system in the news piece.  It is as if we are in a parallel universe, pretending that politicians and bureaucrats can do the job of psychiatrists without any training.  They can turn around and ration access to psychiatrists and then blame psychiatrists for all of the problems they have created.    Luckily,  I have been writing about this curious set of circumstances here for a few years.  You can follow my commentary in the links below and see how it compares to the skewed news version.

The additional question any reader should ask is why psychiatrists are never consulted and why attorneys and bureaucrats with no psychiatric training are in charge of these facilities?  This the cultural trend that started 30 years ago.  Throw out the doctors and run the healthcare system with politicians and bureaucrats that tell the doctors what to do.  Make is seem like doctors in state hospitals can operate in a vacuum rather than on teams and have the bureaucrats tell them how to manage clinical problems.  For a good portion of that 30 year period the word on the street was that the State of Minnesota was shutting down state hospitals and they were going to shut down AMRTC.  Those rumors do not inspire the confidence or commitment from medical or nursing professionals that you need to build a first rate state hospital system.  Who wants to go through credentialing and all that professional applications involve to apply to a hospital that is rumored to be closing soon?

The problem in Minnesota is not about trusting psychiatrists, no matter how bad a media article attempts to portray them.  This article is about trusting the politicians and bureaucrats that run this system.  In 30 years those politicians and bureaucrats have done nothing to merit anyone's trust in managing the public system of mental health care.  The failed state mental health system in Minnesota is an excellent example of what happens when you leave the management of a profession up to amateurs.


George Dawson, MD, DFAPA



Previous posts on the management deficiencies in the Minnesota state mental health system (click on the last word in each line for the post):


Executive Order: No Psychiatrists On Governor's Task Force On Mental Health [ 5/4/2016 ]

Minnesota's Mental Health Crisis - The Logical Conclusion of 30 years of Rationing [11/2/2015 ]

Minnesota State Hospitals Need To Be Managed To Minimize Aggression [1/6/2016 ]

Minnesota Psychiatrist Workforce Shortage [12/2/2015 ]

The CMS Investigation Of Anoka Metro Regional Treatment Center [1/19/2016 ]

Minnesota Finally Rejects Managed Care [5/29/2015]

More On Violence And Aggression In Minnesota Hospitals [12/11/2014 ]

Minnesota Continues A Flawed Approach To Serious Mental Illness And Aggression [12/9/2014 ]

The Shadow State Hospital System [ 11/6/2014 ]

Conflict Of Interest, Primitive Defenses, And Celebrity Death

I don't think there is any good way to say it.  Minnesota's greatest celebrity died recently.  I am not going to use his name or picture on this blog.  It seems fairly obvious that he would not want that.  There was the expected and understandable outpouring of emotion from his tens of millions of fans.  And then he became a projective test for anyone who wanted to sell their idea or opinion or get exposure in the press.  Some of those ideas and exposures included:

1.  The opioid epidemic - he is another statistic.
2.  Opioids are bad drugs and they can kill you.
3.  We could have saved him if he went into treatment.
4.  We could have saved him with Suboxone.
5.  Public scorns buprenorphine (Suboxone) - a medication that could have saved him.
6.  We could have saved him with a treatment intervention.
7.  His problem wasn't addiction at all it was chronic pain.
8.  We could have saved him by treating his chronic pain.
9.  The doctors prescribing these medications need to be disciplined.
10.  The people designated to save him - should have saved him.
11.  His death was "pathetic".
12.  That publicity rights legislation that exceeds copyright protection is necessary for the heirs.

None of these ideas are my ideas and I am sure that by the time you read it - this list is incomplete and outdated.  This is what I have heard or read about his death since it happened.  Some of the dynamics are familiar to me.  The gossip columnists and sites trying to show that they have special contacts and insight and therefore may be more important than other gossip sites.  The insiders proclaiming special knowledge that only a person very close to the celebrity could have.  The very human tendency for some to celebrate the death of those with special talents and capabilities that none of the rest of us have.  Death seems like the ultimate revenge of the mediocre and personality disordered - the final verification that a high flying person dies just like the rest of us.  The entire debacle reminds of a sentence I read somewhere (the reference eludes me): "Only a primitive man celebrates the death of his enemy."  How primitive would the man need to be in order to feel elevated by the death of a superstar?  I realize that these more drastic formulations may be rare.  What fuels all of the controversy?  Some may say morbid curiosity.  They are compelled to look at adverse outcomes whether it is a car wreck on the side of the road or a celebrity death under various circumstances.  It still comes around to what one of my psychoanalytic supervisors described as the most primitive underlying and unspoken thought: "Better him than me!"  The first time an analyst told me that I was somewhat taken aback and then over time I noticed that he was right.  I expected to hear this kind of attitude from non-professionals but not from physicians.  It turned out that I could hear that attitude from a broad spectrum of people.

My biases tend to be at the other end of the spectrum.  I see special capabilities as a celebration of what human beings can do.  Whether that is in athletics, entertainment, art, or my co-workers doing the job in a way that nobody else can do it.  Individual talent and unique capabilities are there to be celebrated and not envied.  I discussed this in an earlier post where the concept is that even people who aren't soccer fans can appreciate the greatness of Pele and just by watching him realize that we are all lifted up by that performance.  Envy seems like a marker that we should all use to determine our own sense of self and our own boundaries.    

In today's conflict-of-interest morality analysis anyone wanting to capitalize on the reputation of the celebrity to sell their wares escapes criticism.  The people involved will say that this is the price of celebrity and if you did not want everything that went along with celebrity you should have avoided it.  You are protesting too loudly when your privacy is invaded in real life or after you die.  There is another argument that the fans are entitled to this information.  To me that would depend on who is dispensing it and what was their reason.  There are numerous analyses of this problem from the perspective of defense mechanisms and the study of life satisfaction based on the level of those defenses.  Defense mechanisms may be interesting to psychiatrists and other mental health professionals but I don't think that they have to be brought out for this discussion.  At some point in life everyone needs to take a close look at how they interpret both misfortunes and good fortunes of others.  What does it really mean to them?  What does it indicate about their philosophy of life?  What does it mean about their life satisfaction?  When you do that - I think that most reasonable people stop for accidents because they are there to help.  They are not spectators.  Human consciousness has the unique property of allowing us to imagine good and bad things happening to us without having to see the real thing happening to somebody else.

I hope that at some point the culture can move past the all too predictable sequence of self aggrandizement and the obvious conflict-of-interest that occurs when a celebrity dies.  Human life and human achievement is worth celebrating and just like a single person can make us all better or at least feel better - it doesn't take much to bring us back down.  In order to break out of these predictable patterns, it takes a conscious awareness of better ways to be or exist in life and that includes examining and rejecting reasons for continuing the old patterns.

I will personally remember his shining star and some of the accolades from the top performers in his field.  He was truly one of a kind and his art was uplifting to me.  


George Dawson, MD, DFAPA

Latest on Ketamine

(R,S)-ketamine

Ketamine has been prominent in the psychiatric literature and conferences for the past decade as a potential agent for both treatment resistant depression and a rapid antidepressant response.  In some communities ketamine infusion clinics are available where patient can go for a weekly infusion to maintain depression either in remission or a partial response.  At a cultural level, besides being a dissociative agent for anesthesia, ketamine is also in the collection of drugs known as club drugs and as such it is abusable.  Ketamine is not among the most commonly abused drugs.  The NSDUH survey puts lifetime abuse at about 1%.  In a practice of addiction psychiatry it is less likely to be used than LSD and much less likely to be used than dextromethorphan.  It may be one of many drugs used by polysubstance users at some point in their usage history.  Ketamine is also classified as a psychedelic drug or a drug that can cause hallucinogenic or dissociative experiences.  From the time their use was popularized there was a belief that these experiences could be potentially beneficial from the standpoint of personal growth and creativity, as an agent to enhance psychotherapy, or in some cases as an agent to treat psychiatric problems like alcoholism and depression.  Ketamine is currently a Schedule III non-narcotic drug on the DEA List of Controlled Substances.  My first professional exposure to the pharmacology of ketamine occurred in basic science courses in medical school in about 1983.  It was taught as part of the pharmacology of anesthesia agents.  It was taught as not being a first line drug at that point because of the side effects of dissociation and anesthesia.  Like most old medications there has been a recent revival of interest for rapid sedation of patients in emergency department settings.  In the linked report it had a more rapid onset of action than the usual agents, but also a significantly higher complication rate.

Alan Schatzberg, MD gave a presentation on ketamine at the University of Wisconsin Annual Update and Advances in Psychiatry in October 2013.  He presented data to show that the effects of intravenous ketamine were acute but not sustained.  Depressed unipolar subjects noticed the antidepressant effects within a few hours and they lasted about one week before returning to baseline depression scores on a standard Hamilton Depression Rating Scale.  In bipolar depression the effects last about 12 days.  He presented the results of an NIMH trial of ketamine in treatment resistant depression.  It was a small multisite trial that compared ketamine (N=47) to midazolam (N=25) as an active placebo.  The primary outcome measure was remission of depressive symptoms at 25 hours and the rates were 63.8% for ketamine versus 28% for midazolam.  Dizziness, blurred vision, nausea/vomiting, headache, and palpitations were the most common side effects acutely and at 24 hours.  There were no episodes of psychosis.  Longer term strategies were presented that might sustain the acute ketamine response including an oral form, repeated infusions, memantine, riluzole, lamotrigine, high dose d-cycloserine, and several new oral agents that were antagonists or partial allosteric modulators of the glutamate receptor, or partial agonist of the NMDA receptor glycine site.  Response to ketamine infusion at 2 hours was shown to be predictive of response and there was a 70% chance of relapse after repeated infusion but this sensitization did not occur at 2 week intervals.  Despite these limitations on therapy there is  Ketamine Advocacy Network that includes a quote about the coming ketamine today tidal wave and a page with this very dim view of psychiatric practice and the intellectual interests of the average or most (?) psychiatrists.  It is not clear to me who writes their pages or who their medical consultants are.

Barry Rittberg, MD gave a presentation at the Minnesota Psychiatric Society in May 2014 and reviewed the science, clinical trial data, and local protocols for ketamine infusions in Minnesota.  The major problems were short term benefit, unknown long term risk,  inability to drive that day,  psychotomimetic effects, and the 3-4 hour time commitment for the infusion.  The protocol discussed involved a 40 minute infusion with monitoring blood pressure, pulse and oxygen saturations every 15 minutes.  Treatments were given 3 days a week for three weeks.  In addition, insurance companies did not cover the treatment (and still don't).  The treatment is not FDA approved and therefore considered experimental by insurance companies.  

The main emphasis of research studies on ketamine and other agents is the potential importance of the glutamatergic system in the treatment of depression.  It also has a purported role in schizophrenia.  There was a good review in an excellent journal Clinical Pharmacokinetics that suggested the (S)-ketamine had a more favorable side effect profile than the racemate.  It was with that backdrop of information that I honed in on this article that popped up on my Facebook feed.  After the first few pages I knew that I was not going to be disappointed.

The authors of a Nature article (1) review the information in the above paragraphs as a rationale for their research and rapidly describe their series of experiments.  The animal research done in this paper is all rodent research to test the potential antidepressant, self-administration, drug discrimination, chronic corticosterone induced anhedonia, and motor coordination effects effects of various glutamatergic compounds.  All of these paradigms and much more are detailed in the supplementary and methods section of the online paper.  Tissue distribution and clearance of ketamine and metabolites was determined in both plasma and brain at 10, 30, 60, and 240 minutes post ketamine administration.

In the first set of experiments, the researchers showed that (R)-ketamine had greater antidepressant potency in three antidepressant predictive tasks - the mouse forced swim test (FST), the novelty-suppressed feeding task (NSF) and the learned helplessness task.  They also showed that this was not due to higher brain levels (R)-ketamine versus (S)-ketamine.  The NMDAR antagonist MK-801 was also shown to not exert the same effects as ketamine, suggesting that the mechanism was more complex than inhibition.  The most interesting part of this paper was the examination of ketamine metabolites and their potency as potential antidepressants.  Ketamine is metabolized by CYP3A and CYP2B6 hepatic enzymes mostly to norketamine, but a number of transformations including dehydrogenation, and hydroxylation to a broad array of metabolites as shown in the authors' graphic below (click on the graphic for a more readable version).

The HNK (hydroxynorketamine) metabolites are the major metabolites found in the plasma and brains of mice after ketamine administration and the plasma of humans.  When greater antidepressant effects were noted in female mice, it was determined that the levels of (2S,2S;2R,6R)-HNK were three times higher in females than males.  In order to confirm that this metabolite was the most potent, a deuterated form of ketamine was synthesized.  The deuteration significantly slowed the metabolism of the parent compound and the antidepressant effects were eliminated largely by blocking the formation of  (2S,2S;2R,6R)-HNK.  The (2R,6R)-HNK derived from (R)-ketamine was subsequently determined to be the most potent metabolite (as highlighted in the above metabolic map).

The authors went on to confirm that (2R,6R)-HNK increased glutamatergic signalling in a number of paradigms.  They also demonstrated that administration led to expected changes in AMPARS (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors).  Drug discrimination and self-administration tests showed no tendency for self-administration with the (2R,6R)-HNK as opposed to ketamine.  In the same experiments ketamine was self administered and increased amounts were taken.   The (2R,6R)-HNK metabolite also did not cause motor incoordination or increased locomotion like ketamine did.

The implications of this paper are far reaching in terms of possible therapeutic agents.  It clarifies that the molecule involved in treating depression may be a significantly different structure than ketamine.  Second, that structure seems to have none of the side effects of the parent compound in animal models.  This paper also has implications for human research.  A search on HNK in the medical literature shows no evidence that it has ever been administered to humans.  A search on ClinicalTrials.gov shows no current research with the compound.  People are receiving infusions of ketamine for both chronic pain and chronic depression.  The infusions are done in clinics where patients need to monitored closely largely because of the side effects of ketamine.  The research done in this paper suggests that the administration of the active metabolite of ketamine may open the door for a less invasive and time intensive treatment for chronic depression.  I liked the idea that this paper discussed the relevant chemistry and pharmacology - undergraduate and medical school knowledge that is still relevant.  I also liked the idea that it potentially demystifies a hallucinogenic drug.  I have seen the newspaper headlines: "Club drugs to treat your depression."  I doubt that they will be replaced by: "(2R,6R)-HNK to treat your depression" anytime soon.

But the nullification of another urban drug legend is always a positive from my perspective.


George Dawson, MD, DFAPA      



References:

1: Zanos P, Moaddel R, Morris PJ, Georgiou P, Fischell J, Elmer GI, Alkondon M, Yuan P, Pribut HJ, Singh NS, Dossou KS, Fang Y, Huang XP, Mayo CL, Wainer IW, Albuquerque EX, Thompson SM, Thomas CJ, Zarate CA Jr, Gould TD. NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature. 2016 May 4. doi: 10.1038/nature17998. [Epub ahead of print] PubMed PMID:27144355.

2: Peltoniemi MA, Hagelberg NM, Olkkola KT, Saari TI. Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy. Clin Pharmacokinet. 2016 Mar 30. [Epub ahead of print] Review. PubMed PMID: 27028535.

Supplementary:

1:  The figure labelled Extended Data Figure 1 is from reference number 1 (above) and is used with permission from the Nature Publishing Group - license number 3863110054693 obtained on May 6, 2016.

2:  Shortly after writing this post I came across this reference suggesting the postsynaptic signalling mechanism responsible for the "ketamine" effect.  I have not read the article yet since it is not open access, but if they were really using ketamine to induce the effect it would be more interesting if they compared (2R,6R)-HNK to ketamine and other metabolites in this model.  It could provide confirmatory data on whether (2R,6R)-HNK is in fact the active metabolite.

Harraz MM, Tyagi R, Cortés P, Snyder SH. Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation. Mol Psychiatry. 2016 Mar;21(3):313-9. doi: 10.1038/mp.2015.211. Epub 2016 Jan 19. PubMed PMID: 26782056.

Executive Order: No Psychiatrists On Governor's Task Force On Mental Health

I received an e-mail two days ago from the current President of the Minnesota Psychiatric Society on the formation of a Governor's Task Force On Mental Health.  That e-mail commented that no psychiatrists were considered for the Task Force, but that psychiatrists could apply as concerned citizens and were encouraged to do so.  I have done this in the past and been ignored so I was not eager to repeat that again.

The public mental health system in Minnesota has been seriously mismanaged and ignored for the past 30 years or about as long as I have been a psychiatrist in this state.  During that time, I have witnessed a long string of bureaucrats with no specific experience trying to manage a state hospital system or more likely trying to shut it down.  Those efforts were seriously compromised by some of the same legislators who decided to develop a system of civil commitment for sex offenders because they thought it would be easier to detain them on a dangerousness standard than the usual legal criteria.  Let's forget about the commitment standard that suggests the person should have a treatable illness.  The efforts to shut down the state hospital system were also compromised by the fact that the system really started to backfire when the number of available beds in Minnesota dropped to the lowest number in the US.  At that point there was always a large pool of unstable patients circulating between the emergency department, brief inpatient stays where not much happened, and the street.  During that time significant housing resources for both adults and children with significant psychiatric problems was shut down.

The icing on the cake from the State Legislature was their myopic approach to the problem of the mentally ill being incarcerated.  They "solved" the problem by coming up with a rule that any county jail inmate could be transferred to Anoka Metro Regional Treatment Center (AMRTC) within 48 hours.  AMRTC was supposed to the the remaining flagship public psychiatric hospital for patients with no forensic problems, that is they had not committed a violent crime due to mental illness.  This was a predictable double whammy, sending violent inmates to a hospital setting and short circuiting long waiting lists of patients waiting to get to AMRTC as a result of commitments at community hospitals.  This has led to a record number of assaults on staff working at AMRTC, at a time when nurse manager staff critical in managing aggression had been downsized.

Community mental health centers (CMHCS) have certainly not fared any better.  At some point the decision was made that they could be treated like managed care clinics.  In other words they would be funded by staff "productivity" and practice medication rather than psychotherapy focused services.  Even then, reimbursement from traditional funding sources was so poor or so entangled in unnecessary paperwork that the funding was inadequate to keep the doors open.  Some CMHCs have just gone out of business and advised their patients to see primary care physicians or distant mental health clinics.  People generally do not drive long distances to be seen, at least not for very long.  It is hard enough to drive across town, much less several hours for an appointment.

Looking at the goals of the Mental Health Task force and who the Governor wants on it - it is clear that this is a serious committee with a serious mandate to develop a continuum of care and the supporting infrastructure with funding sources.  The political and managerial members of the Task Force are carefully specified.   Why then would representatives of the same failed agencies from the past be appointed to serve on it?  Why are there no psychiatrists or psychiatric nurses - linchpins of what can be loosely described as this system of care?  Why are there no psychiatric social workers - the people with the most experience in dealing with the glaring lack of resources?  These are the people who know what the problems are, how they can be solved, and what they have to put up with every time a state politician or bureaucrat makes another bad decision.  And yet none of these groups are specified Task Force members.

The implicit question is how many times these state government driven processes need to fail before there is a rational process?  One of the associated questions I dealt with as the President of the Minnesota Psychiatric Society is why professional organizations in the state always seem to fall silent about these processes every time they occur.  There are psychiatrists employed in these systems that may not want to hear any criticism from their professional organization about the overall processes, and that is something I have never really understood.  There are certainly plenty of professionals who avoid contact with these systems entirely.  It is one thing to have to try to function very day at work in an environment where doing the work is impossible due to financial and bureaucratic constraints.  It should be fairly obvious that is not a personal criticism of any employee in that system.   It is well past the time when the professional organizations represented in these systems get involved and tell whatever Task Force coming down the pike what is necessary to provide quality care to people with severe mental illnesses.

Until that time comes, I encourage every psychiatrist in the state to use my standard answer about why the mentally ill in this state get rationed and inadequate treatment:

"This decisions in this state are made by people who know considerably less about it than I do."

That is just the way we do business in the USA right now.  At some point the American people were sold the idea that managers with no particular skill other than declaring themselves to be managers were what we needed to solve problems.  Being a politician or a manager seems to trump just about every technical skill, but in this case the resulting problems have been more than a little glaring.  Knowing how to treat the severe mental illnesses that are seen in state hospitals and CMHCs requires more than an MBA or JD.  You have to be well trained and know what you are doing.

This Task Force seems to be a collection of what has come to be called stakeholders and it is more than a little ironic that this group never seems to include the people who show up each day to do the work. 


George Dawson, MD, DLFAPA


Reference:

Here is the original Executive Order - dated April 27, 2016.


Supplementary 1:

A rich source of political rhetoric that is frequently used against professionals by managers is: "Let's see you come up with a solution."  They never really step aside and let the professionals manage.  They are just trying to shut them up.  Well here are a few ideas for starters that I will put up right now against any Task Force product.  And I am the only stakeholder writing this blog:

Minnesota State Hospitals Need To Be Managed to Minimize Aggression - link

Minnesota's Mental Health Crisis - The Logical Conclusion of 30 Years Of Rationing - link

Minnesota Continues A Flawed Approach To Serious Mental Illness And Aggression - link

Public Sector Mental Health Continues to Be Squeezed Out Of Business - link







 

The Medical Cannabis Smorgasbord In Minnesota

I took in a CME course on Medical Cannabis: Clinical Applications and Evidence for Health Professionals on April 28, 2016 8 AM - 5 PM.  It was done as a collaboration between the University of Minnesota Center for Spirituality and Healing and The Minnesota Department of Health Office of Medical Cannabis.  Minnesota was the 22nd state to legislate a version of medical cannabis and this conference showcased the Minnesota version, the state and federal regulatory landscape, the available evidence to support the use of cannabis in certain conditions.  The politics of medical cannabis was also on display with viewpoints by some of the experts on the panel that represented scientific data, but also complementary approaches that had very little to do with science.

The Minnesota approach is an interesting one, because it may prove to provide the only cannabis products that offer a relatively standardized dose of tetrahydrocannabinol (THC), cannabidiol (CBD) or some combination.  In Minnesota there are two companies that are the exclusive providers of non-smokable cannabis products that are extracted from the entire plant - Leafline Labs and Minnesota Medical Solutions.  The extraction process is entirely carbon dioxide based and no hydrocarbons are used.  There are strict quality control measures.  There are no smokable or combustible cannabis products in the state.  According the statute, medical cannabis is available only as "oil, pill, vapor (oil or liquid but not dried leaves or plant form) or any other form approved by the commissioner excluding smoking".  These two companies supply state operated pharmacies that dispense only the cannabis products.  In order for a person to access these products they need to register with the state, pay a $200 annual fee, be certified as having an eligible condition by a physician who recommends rather than prescribes the product.  The patient discusses the actual product to be used with the pharmacist and pays for the product.  There are no insurance companies or state programs that pay for the cannabis.

The speakers at this venue were highly qualified.  Donald Abrams, MD is an adult oncologist with 32 years experience.  He gave lectures on "Medical Cannabis and the Endocannabinoid System" and "Clinical Applications of Cannabis: Cancer Care."  Both were highly informative.  He is one of the few people to access cannabis that is grown by NIDA (National Institute of Drug Abuse) and go through the regulatory maze that allows researchers to use it in clinical trials.  He discussed a concept that I had never heard of before called the entourage effect.  The entourage effect was defined as the benefits of using the whole cannabis plant rather than the more specific compounds.  The theory is that there are compounds in the broad mix that enhance the overall effect of the more active ingredients by both pharmacokinetic and pharmacodynamic effects.  He described this as one of the principles of Chinese medicine, which of course is not the allopathic medicine that we all practice in the US.  He emphasized the benefits of delivery as smoke or vapor rather than oral forms largely due to rapid onset of action and more rapid adjustment of the dose compared with oral forms.  He presented data to show that a particular volcano style vaporizer can consistently deliver therapeutic amounts of cannabis to the patient.  Once that was determined, that was the recommended delivery system for his patients.

Michael Bostwick, MD a Mayo Clinic psychiatrist gave two excellent presentations on "Medical Cannabis: Barriers, Myths, and Evidence" and "Medical Cannabis Statutes and the Role of the Federal Government".  One of the biases discussed by Dr. Bostwick in the seminar was the common observation that advocates see cannabis as a cure for everything when there is scant data that it is useful for the indicated conditions.  Of course that bias may also reflect the mixed agenda of recreational cannabis advocates seeking to legitimize cannabis as medicine and open the door for eventual widespread legalization.  In that endeavor, science would be an expected casualty.  The other bias was hysteria over the adverse medical and societal effects of cannabis use and how at least some of those attitudes may have resulted from racist attitudes in the 1950s.  Images from Reefer Madness were shown, as being emblematic of the spirit of the times.  That exercise does have a much different meaning today.  A good portion of the audience was all seeing and all knowing - eager to laugh at the ignorance of this archaic movie and applaud any speaker who advocated for the removal of all barriers to medical (and non-medical) cannabis use.  The problem is that I was sitting in an audience watching Reefer Madness in 1973 who were acting the same way.  The bottom line is that, these biases have clear effects on legislation and that led to cannabis going from being listed on the US Pharmacopeia for a hundred years to Schedule I on the DEA list of Controlled Substances.  A countervailing fact is that cannabis has been around for 5,000 years and has no clear medical indication.  That was mentioned as a historical fact, but not as a potential rationale for the Schedule I listing.  There was plenty of optimism that the discovery of the endocannabinoid system and getting cannabis off the most restrictive controlled substance category would lead to a whole new era of useful medicinal compounds.

Dr. Bostwick's discussion of the regulatory landscape of cannabis was superb.  I teach this subject myself and he was somehow aware of two more memos from the Justice Department than I was on the practical aspects of enforcing the Controlled Substances Act in the context of increasing legalization at the state level.  He described this as the states "going rogue" which I thought was humorous.  He also carefully laid out the FDA regulatory process and how it is not really set up the approval of botanicals or researchers interested in using cannabis for research purposes.

Ilo Leppik, MD is a long time neurologist and epileptologist in the Twin Cities.  Thirty three years ago when I was an intern on one of the neurology services in town and he was an attending physician.  At about that time, he noticed some basic science research about CBD having potential anticonvulsant properties.  He tried unsuccessfully to get pharmaceutical companies interested in this compound for years.  He discussed the currently available research and the single company that is trying to get FDA approval for a cannabis derived approach to treating seizures.  He is also an advocate for getting all of his neurological colleagues involved as registered certifiers of medical cannabis.  Epileptologists treat refractory seizure disorders that do not adequately respond to other measures and in this population Dr. Leppik would use medical cannabis and he presented the supporting data.

 The well known publicized case of the pediatric patient with seizures was discussed by Dr. Leppik.  This case is frequently cited by pro-cannabis advocates as proof that cannabis is a legitimate medication that needs broader use.  He pointed out that this patient not only did not have the seizure disorder that he was purported to have (Dravet Syndrome) but that he also had not seen the top epileptologist in the state where he resided.  He went on to present a case from his own practice where childhood epilepsy was misdiagnosed.  He made the correct diagnosis, but at that point, the patient's mother insisted that he stay on CBD along with the correct anticonvulsant for the condition.  The patient eventually ran out of the CBD, but the seizures remained in remission because he had been put on the correct standard anticonvulsant for the correct diagnosis - in this case valproate.

Angela Birnbaum, PhD is a pharmacologist and presented the most science of the day.  Straightforward pharmacokinetic principles and how they apply to treating patients with epilepsy.  Her approach also highlighted the advantages of using the Minnesota approach to medical cannabis and being the only way to assure steady levels of the drug necessary to treat epilepsy.  Dr. Birnbaum also presented a graphic similar to the one below on the product types available from the Minnesota companies.  More detailed information is available at the company web sites shown above.

Susan Sencer, MD presented medical cannabis from the perspective of a pediatric oncologist.  With the relatively new medical cannabis laws in Minnesota, her pediatric hospital has certified its use in 19 pediatric patients all with cancer diagnoses.          

To a guy who has been an acute care psychiatrist and an addiction psychiatrist all of his working life, there were clearly some biases operating at this conference that very few people seemed to be aware of.  Cannabis was discussed as a nearly benign product.  Sure we know the endocannabinoid system has something to do with brain development, and sure it could lead to psychosis and early onset of psychosis but probably only in people who were predisposed to psychosis.  There were remarks that none of the panelists who recommended medical cannabis and followed adult patients on that cannabis had ever seen any of them develop an acute psychosis.  There were jokes made about the implausibility of amotivational syndrome.  In the opinion of the panelists side effects were generally benign, even though data was presented from clinical trials suggesting otherwise.  As I looked at the clinicians represented on the panel who treated patients with cannabis there were two oncologists, a neurologist, and a psychiatrist who specialized in treating chronic pain.  Only the psychiatrist talked about treating some people with psychotic disorders and at one point there was a slide that suggested chronic psychotic disorders might be a contraindication to the use of cannabis.  The data presented and the description of the practices suggested to me that there was a strong selection bias present.  The panelists were not seeing psychiatric complications or problems with addictions because they weren't treating anyone with psychiatric disorders or addictions.  Guys like me see those patients and the last thing we want to see is somebody giving our patients cannabis.  I think that it will be a much different story if the list of eligible conditions is expanded to include insomnia, anxiety, depression, and posttraumatic stress disorder like it is in some states and the list of medical personnel authorized to certify the use of medical cannabis expands.  Just expanding the indication to chronic pain will bring in a patient population that is probably distinctly different from the patient base that the panelists are treating.

As I have written on this blog many times before, I don't like the idea of medical cannabis for the exact same reason that one of the panelists mentioned - it always has been a political manipulation for the legalization of recreational marijuana.  If you want to advocate for the legalization of recreational marijuana that is fine with me, but don't drag physicians into it and pretend it is an allopathic medicine.  That reference came out at the conference many times when it was referred to as a "botanical" and therefore very awkward in the FDA regulatory scheme.  At the same time, I have no problem with oncologists or neurologists telling their patients to use it.  But I am not going to pretend that there is not significant psychiatric morbidity that extends far beyond activating psychosis in those who are predisposed.  And I imagine that many of my colleagues will find this out when they discover that some of their patients now have cannabis added to their list of medications and that many of the panelists will discover this if they start seeing significant numbers of patients with psychiatric problems and addictions.

Despite all of the politics and bias - there is some underlying science that supports medical cannabis and Minnesota has the most rational approach toward implementing it.  Addiction and the psychiatric side effects of these compounds will always be a limiting factor for some.   In that case - as in the case of every other addicting medication - the best solution is to avoid it and try something else.


George Dawson, MD, DFAPA

References:

1: Bostwick JM. We need to reschedule cannabis. A sane solution to an irrational standoff. Minn Med. 2014 Apr;97(4):36-7. PubMed PMID: 24868930.

2: Bostwick JM. The use of cannabis for management of chronic pain. Gen Hosp Psychiatry. 2014 Jan-Feb;36(1):2-3. doi: 10.1016/j.genhosppsych.2013.08.004. Epub 2013 Oct 1. PubMed PMID: 24091257. 

3: Bostwick JM, Reisfield GM, DuPont RL. Clinical decisions. Medicinal use of marijuana. N Engl J Med. 2013 Feb 28;368(9):866-8. doi: 10.1056/NEJMclde1300970. Epub 2013 Feb 20. PubMed PMID: 23425133. 

4: Bostwick JM. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc. 2012 Feb;87(2):172-86. doi: 10.1016/j.mayocp.2011.10.003. Review. PubMed PMID: 22305029; PubMed Central PMCID: PMC3538401.

5: Abrams DI, Guzman M. Cannabis in cancer care. Clin Pharmacol Ther. 2015 Jun;97(6):575-86. doi: 10.1002/cpt.108. Epub 2015 Apr 17. Review. PubMed PMID: 25777363. 

6: Hazekamp A, Ware MA, Muller-Vahl KR, Abrams D, Grotenhermen F. The medicinal use of cannabis and cannabinoids--an international cross-sectional survey on administration forms. J Psychoactive Drugs. 2013 Jul-Aug;45(3):199-210. PubMed PMID: 24175484. 

7: Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011 Dec;90(6):844-51. doi: 10.1038/clpt.2011.188. Epub 2011 Nov 2. PubMed PMID: 22048225. 

8: Carter GT, Flanagan AM, Earleywine M, Abrams DI, Aggarwal SK, Grinspoon L. Cannabis in palliative medicine: improving care and reducing opioid-related morbidity. Am J Hosp Palliat Care. 2011 Aug;28(5):297-303. doi: 10.1177/1049909111402318. Epub 2011 Mar 28. Review. PubMed PMID: 21444324. 

9: Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL. Vaporization as a smokeless cannabis delivery system: a pilot study. Clin Pharmacol Ther. 2007 Nov;82(5):572-8. Epub 2007 Apr 11. PubMed PMID: 17429350. 

10: Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, Kelly ME, Rowbotham MC, Petersen KL. Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007 Feb 13;68(7):515-21. PubMed PMID: 17296917. 

11: Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal cannabis: rational guidelines for dosing. IDrugs. 2004 May;7(5):464-70. Review. PubMed PMID: 15154108. 

12: Andreae MH, Carter GM, Shaparin N, Suslov K, Ellis RJ, Ware MA, Abrams DI, Prasad H, Wilsey B, Indyk D, Johnson M, Sacks HS. Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data. J Pain. 2015 Dec;16(12):1221-32. doi: 10.1016/j.jpain.2015.07.009. Epub 2015 Sep 9. PubMed PMID: 26362106; PubMed Central PMCID: PMC4666747.

13: Arneson T. Insights from a Review of Medical Cannabis Clinical Trials. Minn Med. 2015 Jun;98(6):40-2. Review. PubMed PMID: 26168662.

14:  Health Canada web page consumer information on cannabis.

15:  Health Canada Information for Health Care Professionals Cannabis (marihuana, marijuana) and the cannabinoids - a very highly regarded report by the panelists at this conference.  This is the 2013 version and a 2016 update is pending at this time.

16: Katona I. Cannabis and Endocannabinoid Signaling in Epilepsy. Handb Exp Pharmacol. 2015;231:285-316. doi: 10.1007/978-3-319-20825-1_10. Review. PubMed PMID: 26408165. 

17: Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8. doi: 10.1016/S1474-4422(15)00379-8. Epub 2015 Dec 24. PubMed PMID: 26724101. 

18: Reddy DS, Golub VM. The Pharmacological Basis of Cannabis Therapy for Epilepsy. J Pharmacol Exp Ther. 2016 Apr;357(1):45-55. doi: 10.1124/jpet.115.230151. Epub 2016 Jan 19. PubMed PMID: 26787773. 

19: Tzadok M, Uliel-Siboni S, Linder I, Kramer U, Epstein O, Menascu S, Nissenkorn A, Yosef OB, Hyman E, Granot D, Dor M, Lerman-Sagie T, Ben-Zeev B. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure. 2016 Feb;35:41-4. doi: 10.1016/j.seizure.2016.01.004. Epub 2016 Jan 6. PubMed PMID: 26800377. 

20: Blair RE, Deshpande LS, DeLorenzo RJ. Cannabinoids: is there a potential treatment role in epilepsy? Expert Opin Pharmacother. 2015;16(13):1911-4. Epub 2015 Aug 3. PubMed PMID: 26234319; PubMed Central PMCID: PMC4845642. 

21: Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and Epilepsy. Neurotherapeutics. 2015 Oct;12(4):747-68. doi: 10.1007/s13311-015-0375-5. PubMed PMID: 26282273; PubMed Central PMCID: PMC4604191. 

22: Kaur R, Ambwani SR, Singh S. ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target. Curr Clin Pharmacol. 2016 Apr 17. [Epub ahead of print] PubMed PMID: 27086601. 

23: Leo A, Russo E, Elia M. Cannabidiol and epilepsy: Rationale and therapeutic potential. Pharmacol Res. 2016 Mar 11;107:85-92. doi: 10.1016/j.phrs.2016.03.005. [Epub ahead of print] PubMed PMID: 26976797.

24:  Volkow ND, Baler RD, Compton WM, Weiss SRB.  Adverse Health Effects of Marijuana Use.  N Engl J Med 2014; 370:2219-2227,  June 5, 2014;  DOI: 10.1056/NEJMra1402309

Supplementary 1: At this time (Saturday afternoon) - I am still waiting for the link to all of the presentations.  I do plan to add some detailed information at that point - the above information was only what I can recall from direct observation.  As soon as I have those links I will be able to list the actual medical cannabis products in Minnesota.  They are not available on the Medical Cannabis web site or one the sites of either of the manufacturers.  Stay tuned for a graphic containing all of that information.

Supplementary 2:  One of the jokes about addiction specialists at the conference was that they were like "orthopedic surgeons at the bottom of a ski hill."  The obvious implication is that they only see the train wrecks.  The other implication is that non-addiction specialists can prescribe addictive drugs with with no concerns about addiction and they will usually be OK - that is most people will make it safely to the bottom of the ski hill.  Of course by that time they had already presented data that "only" 9% of people who use cannabis get addicted to it, they are almost all young, and the panelists general impressions that their patients did not have a problem with addiction.  There has never been any disagreement that in terminally ill patients - addiction is not a concern.  Chronic pain patients without a terminal illness have a much different problem.   The ethical problem to me is that there may be an obligation to make sure that the skiers can negotiate the hill before you sell them the ticket.  There is also a recent precedent for declaring that prescribing practices were too conservative based on addiction risk.  That happened right before the current prescription opioid epidemic based on seriously flawed studies of addiction.

Supplementary 3:  If you want the best single reference on this subject - go to the Health Canada monograph (reference 15 above).  Read the currently available document and wait for the 2016 update.  It is a free download.

Supplementary 4:  Marijuana and Cannabinoids - an NIH sponsored neuroscience summit; March 22-23, 2016.  Link to the archived video recordings.