Synthetic Cannabinoids and Life Threatening Coagulopathy

Just when I thought that renal failure was the only unexpected complication of synthetic cannabinoids - it turns out they can also cause bleeding or more specifically Vitamin K dependent antagonist coagulopathy.   The basic mechanism of action is noted in the above diagram on the action of warfarin on Vitamin K dependent mechanisms that can lead to an anticoagulated state.  Warfarin and similar Vitamin K antagonists block the function of the vitamin K epoxide reductase complex.  That blocks the recycling of Vitamin K epoxide and eventual depletion of Vitamin K.  That is turn leads to no gamma carboxylation of Vitamin K dependent coagulation factors (depicted here as descarboxy prothrombin being converted to prothrombin (Factor II), but factors VII, IX, and X are also involved).  

The anticoagulated state can be used therapeutically to prevent embolic strokes or recurrent pulmonary emboli, but warfarin has a very narrow therapeutic index and it needs to be monitored closely in patients who are also watching their diet and drug interactions to prevent excessive anticoagulation and bleeding that can be fatal. The warfarin effect can be reversed by Vitamin K administration.

The CDC issued an outbreak alert last month about an outbreak that occurred in the midwest - largely Illinois about unexplained bleeding.  The time frame where this was noted was the previous year.  People were presenting to emergency departments with unexplained bleeding ( no exposure to anticoagulants or anticoagulant containing rat poison and no medical explanation for the bleeding).  In their Clinical Action Alert they explain the symptoms of coagulopathy including bleeding from the gums, nose, gastrointestinal tract, genitourinary tract, excessive bruising, unexplained abdominal of flank pain, mental status change, feeling faint, and collapse.  There were a total of two fatalities at the time of the alert and medical evaluation and treatment with Vitamin K and fresh frozen plasma suggested that the toxicity was due to brodifacoum a long acting Vitamin K antagonist found in rat poison.

Ninety four people were involved through April 5, 2018.  Since that time the Illinois web site following this outbreak reports 164 cases including 4 deaths since March 2018.  They name a few of the brands commonly sold including K2, Spice, Black Mamba, Bombay Blue, Genie, and Zohai but emphasize that there are a large number of these compounds as listed in a previous post on this blog.  As previously noted, synthetic cannabinoids are basically highly concentrated organic chemical that are sprayed in plant material to facilitate smoking.  When I checked the medical literature to see if these cases were written up and specific biochemical analyses done - I found the only reference brodifacoum was a study done (1) that looked at the results of applications to areas around marijuana growing operations.  Anticoagulant based rodenticides are apparently used to prevent damage to the crop and are described as being used extensively.  This study looked at marijuana growers on California and the relationship to wildlife species.  In this case a threatened species the northern spotted owl was necropsied and it was demonstrated that the liver and blood contained high concentrations of brodifacoum.  The authors point out a basic ecological principle that if the target of the rodenticide is rodent - it will be concentrated to higher levels in the predators higher in the food chain.  The alarming situation here is the fact that dead wildlife from rodenticide poisoning have been found around 22% of 41 marijuana growers in 3 California counties.

The message from the CDC and the Illinois Department of Public Health (IDPH) was clear.  Be aware of the problem, recognize coaglopathies, and be prepared to intervene.  The IDPH advises consumers to watch for bleeding and bruising if they have used these compounds and if it occurs to seek emergency assistance.  The CDC discusses the high cost of Vitamin K therapy and possible shortages, the need to warn post op patients not to use these compounds, and concern that some of the affected patients may be plasma donors.

Addiction docs and acute care psychiatrists need to have a higher index of suspicion, especially in settings where people are admitted rapidly for detoxification and stabilization and if the patient gives a history of synthetic cannabinoid use.  The commonest current coagulopathy in those settings is probably alcohol related and that is relatively rare.

Additional concerns would include the possibilities that the rodenticide could be sprayed on some cannabis plants and be ingested or smoked by people who believe they are using cannabis.  An associated concern is that the contaminated synthetic material was considered plant waste from cannabis products and just used as a carrier for the synthetic cannabinoids.  That is a potential reason why the synthetics were contaminated with brodifacoum in the first place.

As far as I know there have been no reports of the problem in cannabis smokers who were not using synthetic cannabinoids.

The authors of reference 1 point out that since cannabis is not regulated as an agricultural product there are no regulations about what can be applied to it when it is grown.  It seems like another disadvantage of a laissez-faire approach to drug regulation.

Coagulopathy is just another in a long list of reasons to stay away from synthetic cannabinoids and to beware of other toxic effects from street drugs.  There has always been some concern over what chemicals and biologicals end up in smoked or ingested cannabis. Rodenticide should be added to that list until it is effectively ruled out by sampling and testing of the products being sold.




George Dawson, MD, DFAPA


References:

1:  Franklin AB, Carlson PC, Rex A, Rockweit JT, Garza D, Culhane E, Volker SF,Dusek RJ, Shearn-Bochsler VI, Gabriel MW, Horak KE. Grass is not always greener: rodenticide exposure of a threatened species near marijuana growing operations. BMC Res Notes. 2018 Feb 2;11(1):94. doi: 10.1186/s13104-018-3206-z. PubMed PMID: 29391058;

2: Brodifacoum on ToxNet.

Brodifacoum

3: Minnesota Department of Health.  Health Advisory: Significant Bleeding Associated with Contaminated Synthetic Cannabinoids. April 5, 2018.

4:  Minnesota Department of Health.  Health Advisory Network.  See additional links.  





Graphics:


1:   Mechanism of warfarin slide at the top is from Visiscience slides online per their user agreement.

2:  Brodifacoum chemical structure from PubChem.








 

Relief For the Sleep Deprived?

Sleep is a major problem for the majority of people who I see in clinical practice.  It is both a diagnostic feature and a primary disorder.  It is not uncommon for me to see people in their 30s or 40s who have had consistent sleep problems since childhood.  Environmental, medical problems, and alcohol/substance use are also common causes of insomnia.  After cessation of opioids, cannabis, or alcohol there can be disrupted sleep that lasts for months or longer. The treatment of insomnia is partially effective.  Behavioral methods like sleep hygiene measures and CBTi are useful for some people.  Medications can be helpful but they are a mixed bag for practitioners.  Sleep medications that are typically recommended have significant side effects including tolerance to the sedative effects that can lead to dose escalation and addiction.  The non-FDA approved medications like trazodone are widely used but routinely criticized in the literature for not having enough of an evidence base.  Physicians often face patients who are not sleeping well and ask for practical ways on catching up.  The news media lately has a lot of stories about the dangers of sleep deprivation creating some desperation in the sleep deprived population.  A common question is: "Can a sleep deprived person make up for lost sleep?" 

There was a very interesting study released by a research group this month on sleep and whether or not the sleep deprived can make up for lost sleep on the weekends.  The study looked at 38,015 participants in the Swedish National March Study who returned a general health questionnaire on medical history and lifestyle in 1997.  There were two questions about sleep:

How many hours  approximately, do you sleep during a workday/weekday night?

How many hours approximately, do you sleep per night on days off? 

The authors considered short sleep < 5 hours per night and long sleep > 9 hours per night.  The considered days off to be the equivalent of weekend sleep and simplified the response categories to reduce cells with low numbers of subjects.  The reference category was considered to be 7 hours.  The formed the following 6 categories based on that sleep classification and the pattern over the weekday/weekend (S=short, M=medium, L=-long):  SS, MM, LL, SML, ML, and LS.  Patient were following to the endpoints of death, emigration or study termination on December 31, 2010.

The authors used a Cox proportional hazards model with attained age to estimate mortality hazard ratios and 95% confidence intervals for each group adjusted for a number of variables including sex, BMI, smoking status,  physical activity, alcohol intake, educational level, shift work, and a weighted index based on an inpatient register.

The main finding with the correlations of mortality with short weekend sleep.  For subjects less that the age of 65, short weekend sleep was associated with a hazard ratio (HR) or 1.52 95% CI 1.15-2.02.  In other words subjects with short weekend sleep had a 52% greater mortality rate.  There was no different in mortality for short weekend sleep in subjects older than 65 years of age.  Forest plots were provided to look at adjusted and unadjusted HR across 5 sleep categories (≤ 5 hrs, 6 hrs, 7 hours, 8 hrs, ≥ 9 hrs).  A weekend sleep duration of ≤ 5 hours in subjects less than 65 clearly had the highest mortality ratio. In other analyses short sleep on both the weekdays and weekends and consistently long sleep were also associated with higher mortality.

Interestingly from a psychiatric perspective self reported sleep medication use did not alter the outcomes.  Sleep medication use was reported in every sleep category by 9.5 to 28% of the subjects in those categories (the short sleepers reporting more medication use).  Snoring, napping, restorative sleep, general health and high work demand did not affect results.  The initial model also corrected for shift work.

This is very interesting research because it suggests that there is a way to catch up on sleep debt at least on a short term basis.  Chronic sleep debt like the kind that physicians endure in medical school and residency training is probably gone forever.  But in clinical practice, it is theoretically possible to sleep in on the weekends after getting 5 hour blocks during the week and erase that debt - at least from  mortality standpoint.  Even though the authors seem to be doing a lot of analysis from 12 data points on a survey - the  structure of that data allowed them to look at sleep from a different perspective than it is typically analyzed from.  In their introductory section, they discuss the typical analysis focuses on typical sleep patterns and there are no distinctions between weekday and weekend hours.  Analyzing that data typically results in a J-shaped mortality curve with the highest mortality for too little sleep or a U-shaped mortality curve with highest mortality for too little and too much sleep.

The authors discuss the strength of their study (large N, good follow-up) and the potential weaknesses (misinterpretation of the questions by some subjects). From their exclusion process they did a good job of cleaning up the sample.  Their recommendation for closer follow-up studies on a longitudinal basis with more frequent data points is a good one.  From a clinical perspective, it would be useful to know what the time frame is that would allow for the cancellation of sleep debt.  Does it all have to happen in the space of a week or can you sleep very long at the end of two or three weeks and get back on track?  There may be some insights from people with prolonged insomnia from substance use (cannabis, methamphetamine, opioids, alcohol) and how they recover.


George Dawson, MD, DFAPA

References:

1:  Åkerstedt T, Ghilotti F, Grotta A, Zhao H, Adami HO, Trolle-Lagerros Y, Bellocco R. Sleep duration and mortality - Does weekend sleep matter? J Sleep Res. 2018 May 22:e12712. doi: 10.1111/jsr.12712. [Epub ahead of print] PubMed PMID: 29790200.



Graphic:

Sleep duration on successive nights from the smartphone of a person who is off work on the 19th and the 24th and works 20-23 - showing total hours of sleep as 8.19, 5.15, 5.51, 5.45, 5.49, 8.17.  This is a workday/weekend pattern described by the authors in the study.

Wish I Had Said Some More About The Violence......

I shot a video for the 100 Miles 100 Stories charity yesterday.  Their mission is raise awareness for violence against healthcare workers.  They found me through a nurse that I used to work with who sustained a traumatic brain injury when she was assaulted in an emergency department.  The sequelae of that injury ended her career in nursing. The focus of this charity is to raise public awareness of the problem and hopefully find some solutions.  As I have posted on this blog many times, these incidents are generally preventable, but it requires both expertise and a major revision of the systems that most health professional work in every day. I had a meeting two weeks ago on the comments I could make in this area and the interview questions were based on that meeting.  I don't have a transcript or tape and the final version will be edited.  This is my recollection of what happened:

Q:  Tell us about your experience.

A:  I have been a psychiatrist for 32 years and about 22 of those years have been in acute care psychiatric settings at what is now called Regions Hospital.  It used to be St. Paul-Ramsey Medical Center before it was acquired by HealthPartners.  For about 8 of those years a neurologist and I ran a clinic for Alzheimer's Disease and other dementias.

Q:  What kind of psychiatric diagnoses did you see?

A:  Bipolar disorder, major depression, schizophrenia, schizoaffective disorder, personality disorders with a significant overlay of alcohol and substance use.

Q:  Were you ever assaulted?

A:  I was punched three times but there was no serious injury.  Threatening behavior was more a problem.  There were homicidal threats that had the most significant impact on me long term.  As an example, I started to be more conscious of home security and have home security and close circuit TV cameras installed.

The interview is biased on a personal point of view.  If I had been thinking more I could have mentioned what I had seen.  One psychiatrist punched and knocked out.  Another psychiatrist beaten up with a resulting career ending traumatic brain injury. Various injuries to nursing staff and nursing assistants who have the majority of contact with agitated and potentially aggressive patients.  One evening I was talking with nursing staff behind a window that we believed was shatterproof glass. Without warning the window exploded as a heavy chair sailed through it.  Being one step away from very serious injuries and deaths in many situations, but the downside is that may have seemed like an embellishment so I left it out.

Q:  Why do you think it is happening?

There are several reasons.  The lengths of stays in psychiatric units these days is either too long or too short.  People are discharged in 3 or 4 days or they are waiting there for weeks or months to go to a state hospital bed because they are committed.  Acute care inpatient units are not set up to accommodate people staying there that long.  When I interview people have been discharged from inpatients units they typically tell me that they were sitting around watching TV until they could convince somebody that they are not suicidal.

If we consider a person who is experiencing auditory hallucinations who goes to the emergency department for help they might not get admitted for that problem.  They will probably be told to go to an outpatient appointment in a month or two.  In the meantime - they are untreated and that symptoms gets worse.  If they come into the emergency department again, they may angry the second time.  The current system of care has a large circulating pool of partially stabilized or unstable patients that go between the ED, homelessness and homeless shelters, and acute care hospitals.

I should have used the term dangerousness.  I have written about it countless times on this blog but not in the interview.  Dangerousness is essentially the only way that people get admitted to inpatient psychiatric units any more.  That arbitrary business decision rations access to care for people who have also experienced rationing at a both the community level with less housing and at the state hospital level with a marked reduction is state hospital beds.

Q:  What do you think can be done about it?

Changes have to occur at two levels.  Government and business administrators have to open up access to more beds in both state hospitals and community housing.  There has has to be more enlightened management of those beds.  At the service provider level there needs to be a team approach to the problem.  Frequently if there is an assault related injury, there is a lot of silence and nobody talks about it.  Some splitting can occur and some disciplines may think that it can't happen to them.  The victims may blame themselves and become very isolated.  Administrators at every level need to support clinical teams to address this problem.  There needs to be in house experts to fix the problem and not outside consultants who typically know a lot less about problems and solutions.

Q:  What do you think is important about the 100 Miles 100 Stories Walk?

It raises public awareness about this issue and how it impacts health care workers. It might raise awareness about the expectation that it is part of the job and that many people expect health acre workers to accept it.  Hopefully it will also increase solidarity on this issue.

I should have added my opinion that there needs to be a zero tolerance rule for violence and aggression to healthcare workers.  They are after all doing their job taking care of people.

Q:  Is there anything else that you would like to cover?

I would like to mention that there are basically three groups that become violent in health care settings.  The first is people with severe mental illnesses who are making decisions based on a delusional thought process.  The second are people with acute or chronic intoxication states who are agitated or aggressive based on their use of an intoxicant.  The third group are people with personality disorders where aggression is a strategy or way of life.  Limits needs to be established with this group and they must be held accountable.

The interview ended at that point but there was obviously a lot more that could be said.  Like most people - I write a lot better than I speak.  I am sure that if you see the eventual clips I will be much less articulate and probably confabulated much of what I just wrote.

There is also a time constraint for these interviews and the consideration that the public probably wants to hear about the  general rather than the specific problems or proposed solutions. Certainly nobody has been flocking to this blog over the past years for my suggestions about violence or homicide prevention. 

I doubt that many people are aware of the fact that it is common that patients need to be physically restrained so that they don't injure themselves or anyone else.  I can recall being in an ICU setting when a young man suddenly got out of bed and started swinging an IV pole around his head.  An IV pole has a heavy metal base and anyone struck by that base would have been seriously injured.  He was doing this within a few feet of critically ill patients and the ICU nursing staff.  He was also delirious and completely unable to respond to verbal requests or guidance.  That is an illustration of how rapidly one of these situations can develop and also why there is a necessity for being able to respond to the problem rapidly.

I also might have discussed the informal triage system for dealing with violence or aggression.  In Minnesota not all hospitals will receive patients with this kind of problem.  Not all hospitals train their staff to physically intervene in an appropriate way.  In most health care facilities the training ends at how to approach the potentially aggressive patient and it assumes that the verbal intervention will be successful.  That will not work with very aggressive patients and training needs to include more specific physical measures.

There is also a lot of room to discuss environmental safety plans.  What is the physical design of the clinic or hospital ward?  Can changes in the design configuration provide additional safety for patients and staff.  In some cases it is just putting receptionists in safe areas where they are not in danger from walk ins or aggressive patients.  Does there need to be a law enforcement presence?  What about internal security?  What kind of plan needs to be in place to coordinate all of the personnel in emergencies?

Whatever the focus - these discussions need to get out there for the general public to consider.  The level of injuries to hospital staff and in some cases patients needs to improve greatly.  I emphasize again that the majority of these injuries affect nurses and nursing assistants.  Physicians have been  homicide victims as the result of some of this aggression.

In the cases of conscious directed violence - the perpetrators of that violence need to be prosecuted.  No health care employee should go to work every day fearing assault and in some cases disabling and career ending injuries.   



George Dawson, MD, DFAPA



Supplementary 1:

I was sent this link to an incident of emergency department violence from 1993.  That highlights the chronicity of the problem and the lack of effective solutions.  Quotes from the article:

"Health care workers noted, however, that the incident is only the most recent example of the rising tide of violence that has spilled over into the nation's urban emergency rooms."
and:

"County-USC has been no exception. During the first six months of 1991, for example, security guards at the hospital responded to 1,400 reports of threats or attacks, six of which led to arrests. Among the assailants was a panhandler who approached four nurses in the cafeteria and plunged a pair of suture-removal scissors deep into one nurse's neck."

Supplementary 2:

Here is a link to the video I recorded that was the basis for this post.  It is a 4 minute clip edited down from about 20 minutes of interview material.  I had no role in the recording or editing of the clip.

George Dawson, MD on violence toward healthcare workers in psychiatric settings. Clip. 

Addiction Narratives Versus Reality.......

I recently posted my take on this issue of race in addiction treatment. The main argument that I was responding to was that the current opioid epidemic is whitewashed so to speak. In other words white opioid addicts are considered to be "victims" of the opioid epidemic and black addicts are considered just to be addicts at best and criminalized at worst.  Part of the way that white people are framed as victims is by calling addiction a disease.  The author who I was critiquing at the time suggested that the opioid epidemic was marketed to white people along with the medication (buprenorphine) that would "cure" them.  Further, that buprenorphine was more easily available to white people by the nature of the prescribing requirements.  The article went on to selectively highlight one segment of the population where "non-Hispanic blacks" had a higher rate of overdose deaths, despite the fact that the majority of people dying in most categories were white.  I consider my counterargument to be a solid one and that is - there is no known difference in the biological predisposition to addiction of any kind that is based on race and if that likelihood is equal - the only consideration is who is exposed to the drug.

The racialization of the opioid epidemic picked up more speed over the weekend.  One of the theories proposed was that there were no previous "epidemics" of opioid use and that this is another way to sanitize the problem and make it more acceptable to white people.  The article was written for a newspaper - the Guardian and the headline says it all:  "Amid the opioid epidemic, white means victim, black means addict."  That is the basic thesis that runs through the entire essay.  You are either a white, Christian, Republican racist, who considers himself to be a victim of prescription opioid tablets or drug dealers or the hypocritical structure of American society insults you for being black and an addict.  It is suggested directly in the article that common rationalizations of addicts - the ones that everybody uses irrespective of race or substance are the exclusively used by whites to deny responsibility for addiction.  Self-loathing of the addict is described as though that never happens with white people.  Guilt, shame, and self loathing happens to everyone with an alcohol or drug misuse problem.
          
A couple of the arguments can be debunked at the outset. The idea that the term epidemics is applied only to white people so that they can rationalize being victims ignores the medical literature of the 1970s.  In those days researchers were using the terms epidemics and microepidemics and applying the terms across racial groups (3-6).  Successful naturalistic studies were conducted in both white and black neighborhoods and the success in a Chicago study (6) was  correlated with use of the term medical management.  Those same authors used what they called an infectious disease model for intervening in heroin epidemics (5).  The Chicago study was so successful that it was suggested as an alternative to involuntary treatment (4):

 "This work suggests that heroin addiction can be prevented in many who are at risk; it further suggests that prevention may be possible by using psychological and social concepts based on humanist principles without the use of coercion. The authors' approach deserves close attention not only because it offers hope in the face of a mounting national tragedy but also because of its relevance in the current high-level and little-publicized debate over the use of compulsory urine testing and compulsory treatment of drug dependent persons."   - p.1156
     
It appears that at least in psychiatry - humanism was emphasized as the critical element in treating drug dependent persons (not addicts) as far back as 46 years ago.  The design of the naturalistic study in question was impressive and methadone maintenance treatment was used in a majority of the patients.

The issue of differences in the story about the self perception of a white versus black addict does not have the equivalent empirical basis.  I can say unequivocally that any attitude in treatment about being a "victim" of substance use of any type  would be vigorously confronted by treatment staff.  It is not possible to actively participate in treatment with that attitude.  The same is true of the self loathing patient.  Guilt, shame, and self loathing need to be actively explored and corrected to allow participation in the recovery process.  Both attitudes can lead to distress or increased cravings to use drugs and alcohol and relapse.

What about the contention that cultural differences and disparities are the primary problem with treatment differences.  I refer any interested reader to an in depth analysis of the issues by Coleman Hughes (2) and what he describes as the disparity fallacy - in other words that the difference in outcomes between blacks and whites (or any two groups) is due to discrimination being the causal factor.  He lists an impressive number of examples, but I see the underlying principle as being one of undeterminism (7) that is there are multiple theories to account for differences, and people tend to have a favorite and ignore all of the other possibilities.  There is probably no better example than the race rhetoric around addiction.  The promotion of these arguments ignores the primary causes of addiction - a biological predisposition and exposure to the addictive substance.  I am not suggesting disparities are irrelevant to exposure or treatment access but focusing on them as casual ignores the major factors.           

The continued stories about racial differences in treatment and self perception are not really conducive to reshaping America's addiction treatment landscape.  It misses the big picture that there are no differences in race when it comes to addiction.  Any reasonable treatment approach would disabuse anybody coming through the door who believed they were either a victim or a self-loathing addict.  Identical treatment modalities should be offered irrespective of race and that includes medication assisted treatment of all types, necessary psychiatric and psychological treatment, medical evaluation and treatment, and drug and alcohol counseling focused on recovery.  One of the reasons why addiction is viewed as a chronic illness is the high likelihood of relapse and need for ongoing recovery services and support.  One of the main tenets of any 12-step recovery program based on the AA model is that nobody is turned away. The only requirement for membership is a desire to get sober.   

The real problem with drug and alcohol treatment is not racial disparity. It would be fairly obvious if racial discrimination was occurring in any comprehensive treatment program.  The real problem with drug and alcohol treatment is the lack of standards and consistency in treatment.  The most clear cut example is the availability of detox services.  Some forms of withdrawal are life threatening and need to be immediately recognized and treated.  I doubt that the majority of treatment programs in any state have that capability.  Hospitals have been defunded from providing detox services from anyone who is not experiencing life threatening withdrawal for about 30 years now. That has led to a proliferation of subpar and non-medical county detox facilities where limited to no medical care is rendered.  These kinds of inconsistencies in care occur across the board and it is common to see patients who have not received even basic addiction care - completing a treatment program and being released back to their home setting.

Racism has no place in medicine.  I have discussed the advantages of therapeutic neutrality on these pages before and certainly any physician who is not able to do that should not be practicing medicine in the 21st century.  The psychiatric standard for neutrality is higher.  Psychiatrists in particular are trained to understand cultural differences, but it is not possible to be an expert on every culture.  It is possible to appreciate the person in the room and proceed cautiously enough to assure that culturally sensitive care is being provided.         

In the end, there are clearly ways to prevent and treat addiction. Suggesting that race and the narratives around race are the primary factors that account for addiction or recovery is unfounded.


George Dawson, MD, DFAPA


References:

1:  Brian Broome.  Amid the opioid epidemic, white means victim, black means addict.  April 28, 2018.

2:  Coleman Hughes.  The Racism Treadmill.  Quillette May 14, 2018.

3: DuPont RL, Greene MH. The dynamics of a heroin addiction epidemic. Science.1973 Aug 24;181(4101):716-22. PubMed PMID: 4724929.

4: Freedman DX, Senay EC. Heroin epidemics. JAMA. 1973 Mar 5;223(10):1155-6. PubMed PMID: 4739378. 

5: Hughes PH, Crawford GA. A contagious disease model for researching and intervening in heroin epidemics. Arch Gen Psychiatry. 1972 Aug;27(2):149-55. PubMed PMID: 5042822.

6: Hughes PH, Senay EC, Parker R. The medical management of a heroin epidemic. Arch Gen Psychiatry. 1972 Nov;27(5):585-91. PubMed PMID: 5080286.

7:  Stanford, Kyle, "Underdetermination of Scientific Theory", The Stanford Encyclopedia of Philosophy (Winter 2017 Edition), Edward N. Zalta (ed.), URL = https://plato.stanford.edu/archives/win2017/entries/scientific-underdetermination/.