Package Insert For Epidiolex - Does It Suggest A Problem With Medical Cannabis?

Cannabidiol (C₂₁H₃₀O₂)

Epidiolex was approved by the FDA two weeks ago for Lennox-Gastaut syndrome or Dravet syndrome in patients 2 years of age and older.  Epidiolex is cannabidiol (abbreviated CBD) one of several compounds in the plant Cannabis sativa.   I had a previous post on this compound but that was before the package insert came out.  I like to study package inserts of all of the pharmaceuticals I encounter to prevent unexpected side effects, anticipate drug interactions, look at the current prescribing recommendations, and study all of the safety considerations.  Every drug has a section in that package insert about the pharmacokinetics, pharmacodynamics, and considerations in the case of hepatic or renal impairment.  In some cases there are very specific recommendations for dosing with metabolic impairment or potential drug-drug interactions.  The other interesting aspect in this case is that Epidiolex is considered the first botanical extract to be FDA approved and the first cannabis derived compound.  A significant part of the population considers cannabis to be a benign natural product with none of the usual pharmaceutical concern about organ toxicity and drug interactions.

Reading the actual package insert a few things jump out at me today.  The original indications are the same, but the logical question is whether this medication will be used for off labeling prescribing for other indications.  After hearing one of the top epileptologists  in state talk about the use of cannabinoids for epilepsy, there is also the question of whether the diagnosis is correct.  In that lecture he pointed out that a case example in the news media probably did not have the diagnosis and that the expert in the state who could make that diagnosis was not consulted.

The dosing of the drug is fairly robust going from 5 mg/kg/day up to 20 mg/kg/day.  For a 70 kg man that comes out to a max dose of 1400 mg/day putting it in the range of several other anticonvulsants from different classes.

There are warnings about hepatotoxicity.  Early in the document, it states that some patients will experience elevated liver function tests and in some cases with develop overt side effects leading to drug discontinuation.  Baseline screening is recommended with AST, ALT, and total bilirubin.  Patients with elevated baseline transaminases were more likely to experience further elevation of these tests than those subjects with no baseline elevation.  The Child Pugh classification of severity of liver disease is used as a metric with dose adjustments suggested for mild, moderate, and severe disease.

Thirteen percent of patients had ALT elevations that were three times the upper limit of normal (ULN).  Less than 1% had transaminases that were 20 times the ULN and some patients were hospitalized.  In a third of the cases the transaminase elevation resolved without treatment.  In the other two thirds it resolved with discontinuation of the Epidiolex or the associated anticonvulsant (valproate).

Risk factors (associated drugs - clobazam, valproate), dose, and baseline transaminases) were discussed as well as monitoring.  Given the prevalence of the problem screening transaminases at 1 month, 3 months, and 6 months and as indicated after that.  More importantly - screening for the physical illness from drug induced liver disease ("explained nausea, vomiting, right upper quadrant abdominal pain, fatigue, anorexia, or jaundice and/or dark urine") can lead to further evaluation.  Three scenarios for discontinuing the Epidiolex are recommended:

1.  Transaminase levels greater than 3 times the ULN.

2.  Bilirubin levels greater than 2 times the ULN.

3.  Transaminase levels greater than 5 times the ULN. 

My read of the difference between 1 and 3 is that 1 can be a temporary measure but 3 should be permanent.  In my experience with valproate, I would definitely discontinue with these levels.  That is based on the well validated concern that valproate can cause significant hepatotoxicity. It is still possible that additional trials and post marketing surveillance will show that there is not long term concern with CBD.  In the trials transaminase elevation was the most frequent reason that the drug was discontinued (24% versus 3% on placebo).

Drug interactions noted that could be clinically significant. Epidiolex is metabolized by  CYP3A4 and CYP2C19 so that inhibitors of these enzymes can potentially increase the plasma levels.  Strong inhibitors of CYP3A4 include HIV antivirals, antifungals, and buprenorphine.  There are no strong CYP2C19 inhibitors.

Inducers of the same enzymes can lower Epidiolex levels and the standard inducers of those enzymes are carbamazepine, oxcarbazapine, phenytoin, HIV antivirals, prednisone and glucocorticoids, and St. John's Wort. 

Additional warnings about the use of the drug include somnolence and sedation (32%), suicidal ideation and behavior, hypersensitivity reactions, and the risk of withdrawing an anticonvulsant and need to do it gradually.   Regarding the suicidal ideation and behavior the only data presented was from a large (N=199) pooled analysis of clinical trials.  It is a standard warning on all anticonvulsant drugs and there was nothing specific to Epidiolex or CBD.

Clearly Epidiolex or CBD extracted and used at pharmaceutical doses may have some of the power of pharmaceuticals but also has the same significant side effects.  The side effect profile and drug interaction concerns are very similar to other pharmaceuticals that are used to treat epilepsy. This raises some interesting issues in states like Minnesota where high potency extracts of cannabis are being sold as medical cannabis and there is minimal medical supervision - primarily because there is scant evidence that cannabis extracts are medical treatments.  As I previously observed from the most recent report of the Minnesota medical cannabis program, extracts are being sold in this state that result in the ingestion of 12.2 - 1,439.2 mg/day of CBD.  The middle to high end of that range is clearly in the dose range for Epidiolex and the extracts are not prescribed or monitored by physicians - at least there is no requirement for that to happen.  Looking at all of the available data it is clear that the person taking 1,439.2 mg/day is an outlier and the next cluster of patients is at the 100-200 mg/day range. 

In Minnesota, a medical provider certifies a patient as having a condition that qualifies them for medical cannabis. In the case of this report it is chronic pain.  That patient goes to a medical cannabis dispensary and discusses what they want with a pharmacist.  In the case of high CBD products, as far as I know there is no recommended screening, monitoring, or patient education.  Just based on what I read in the current Epidiolex package insert, if the CBD content of the medical cannabis is in a similar dose range that is the equivalent of taking a new pharmaceutical and making it an over the counter drug.  The neurologists prescribing Epidiolex have good guidance on what needs to be monitored and are undoubtedly very familiar with the compound.  Other physicians including psychiatrists need an awareness of the pharmacology of CBD - especially if the dose is in the range suggested by this package insert.

If it was needed, this seems like further evidence that the miracle of medical cannabis has affected the judgment of many who seem to consider it a benign natural product. It turns out in this case, it can have a therapeutic effect on specific seizures at a significant dose for conditions that did not have many good options.  That treatment comes with clear risks.  The risk is reduced since all of the patients treated for the indicated seizure disorders are being followed by neurologists who specialize in the polypharmacy necessary to treat complex seizure disorders.  That includes monitoring potential drug interactions and toxic effects.  Can we say the same thing for people obtaining it through the medical cannabis program or being prescribed the drug off label?

Medical cannabis needs to be taken as seriously for the side effects as it does for the purported benefits.


George Dawson, MD, DFAPA


Reference:

Full Prescribing Information for Epidiolex. FDA approved package insert.


Supplementary 1:

Any FDA package insert is available online by Googling:  "[Drug name] FDA Package Insert"   The PDF of that drug insert will pop up and you will have access to same the full prescribing information that any physician has.

Supplementary 2:

In Minnesota, there are two companies that are the exclusive providers of non-smokable medical cannabis products Leafline Labs and Minnesota Medical Solutions.  Actual THC and CBD content is available on the web sites of both companies.

Leafline Labs has a vaporization product, a sublingual spray, an oral suspension, and a topical preparation.  The highest concentration of CBD in the oral solution is 20 mg/ml.  Epidiolex is 100 mg/ml.

Minnesota Medical Solutions has similar delivery forms and their oral products are capsules and solutions in both 47.5 mg CBD or 100 mg per milliliter CBD.  The latter is the same as prescription strength Epidiolex.

A Second Look At Recreational Cannabis - Already?

I don't know how many other people are weary of the onslaught of pro-cannabis propaganda over the past two decades.  The goal was clear to me at the outset - legalize marijuana.  I have previously posted that I think there will be legalized marijuana in every state in the United States.  I have also posted that "medical" marijuana or cannabis is basically a front for the legalize recreational marijuana movement.  I am very weary of all of the arguments about how cannabis is a miracle drug, how it will lead to stunning new discoveries, how it will lead to less opioid use and misuse, and all of the permutations of these pseudoscientific arguments.  Many of the legal arguments are just straight off-the-wall.  Those include put all the cannabis dealing cartels out of business, create jobs, and tax it as a great source of tax revenue.  The considerable downsides of adding another intoxicant to the culture seems to be mentioned only by a few psychiatrists who are familiar with a great many of the downsides from treating patients who have been using it for a lot longer than the legalization arguments have been in vogue.

A few of those problems became more evident last week. Colorado Governor John Hickenlooper came on CNN and discussed several correlates of cannabis legalization in Colorado.  Property crimes and violent crimes are up.  The number of homeless in Denver is up and some believe this is a correlate of increased crime.  The number of lethal motor vehicle accidents involving cannabis are up.  He did not mention health care related phenomena including a doubling of cannabis related hospital billing codes, a five-fold increase in cannabis related mental health codes, and an 80% increase in cannabis related calls to poison control centers (3).  Unintentional pediatric exposure to cannabis was also observed (4) to increase.  None of the costs of this medical care has been calculated as an offset of the tax revenue from the cannabis.  Gov. Hickenlooper made the point that recent tax revenues were about $200 million relative to a state budget of $30 billion and about 1/3 of that revenue goes for associated law enforcement and educational activities.  He advised against any state making the decision to legalize cannabis based on a tax revenue argument (5).  The articles in the popular press seem to emphasize the need for flexibility with the great social experiment of recreational cannabis and the Governor seems all for that up to a point.  That point is if it is apparent that the social costs in terms of crime and motor vehicle accidents is really up. At that point he suggests that the current cannabis laws can be reversed. 

Rather than get caught up the old causation versus correlation argument, I can say unequivocally that it is naive to assume that the legalization of another intoxicant would not lead to more problems.  The suggestion that problems would be less and that society will be improved overall by the use of more intoxicants can only be seen as a blatant political ploy.  There will be more accidents, more acute toxicity, and more psychiatric morbidity due to cannabis.  I don't know if Colorado is adding up those costs and trying to compare them to any advantages of legalized cannabis, but I would not be surprised at all if Colorado taxpayers don't incur more liability from cannabis than revenue.

Before any cannabis promoters attempt to teach me about the costs of alcohol - read this blog.  There is more posted here on the costs of alcohol than you will find in most places.  My point is not that alcohol doesn't cost more.  My point is fairly obvious and that is every time you add an intoxicant to society it costs you something.  It is not free or a net benefit.   Once cannabis is legal in all 50 states it will be easier to estimate the total damage.

The other article that came out last week had to do with the 420 holiday and a very interesting plot by Staples and Redelmeirer (see Figure 1).  In this essay the authors look at the 420 holiday which is a celebration of cannabis.  The celebrants gather for mass consumption of cannabis. They studied 25 years of fatal crash data between the hours of 4:20PM and 11:59PM on April 20 and compared the crashes at that time to crashed on control days (April 13 and April 27 during the same time interval).  The Forest Plot below shows the findings across a number of comparisons.

The risk of fatal crashes was higher on 420 and significantly higher for younger drivers. On geographic analysis absolute risk of a fatal crash was highest in New York, Texas, and Georgia.  Relative risk (see original article) was decreased only in Minnesota.  The authors comment that even though the majority of the population does not celebrate 420 (or even know that it exists) the traffic accident risk is similar to what is seen on Super Bowl Sunday and policy makers might want to take this into consideration.  So might anyone interested in the drunken driving issue.  Is it possible that cannabis intoxicated drivers as a population are more impaired than alcohol intoxicated drivers?

Those are the considerations from last week.  I am sure that more will occur as the United States legalizes cannabis in very state and as it becomes a legitimate industry.  An issue flagged by the CDC several years ago was the use of synthetic cannabinoids in order to avoid occupation related drug screens, but their initial data was from a time before cannabis was legalized in Colorado.  And once again this post is not an argument for or against legalization.  I hope that I have been quite explicit in saying that I anticipate widespread legalization of cannabis.

This post and most of the posts on this blog are to document the expected fall out from increasing the amount of intoxicants consumed by the population. It is neither benign or beneficial as suggested by the advocates.   


George Dawson, MD, DFAPA



References:

1: Staples JA, Redelmeier DA. The April 20 Cannabis Celebration and Fatal Traffic Crashes in the United States. JAMA Intern Med. 2018 Apr 1;178(4):569-572. doi: 10.1001/jamainternmed.2017.8298. PubMed PMID: 29435568; PubMed Central PMCID: PMC5876802.

2: Colorado Attorney General Announces Indictment of Massive Illegal Marijuana Trafficking Conspiracy. June 28, 2017.

3: Wang GS, Hall K, Vigil D, Banerji S, Monte A, VanDyke M. Marijuana and acutehealth care contacts in Colorado. Prev Med. 2017 Nov;104:24-30. doi: 10.1016/j.ypmed.2017.03.022. Epub 2017 Mar 30. PubMed PMID: 28365373; PubMed Central PMCID: PMC5623152.

4: Wang GS, Le Lait MC, Deakyne SJ, Bronstein AC, Bajaj L, Roosevelt G.Unintentional Pediatric Exposures to Marijuana in Colorado, 2009-2015. JAMA Pediatr. 2016 Sep 6;170(9):e160971. doi: 10.1001/jamapediatrics.2016.0971. Epub 2016 Sep 6. PubMed PMID: 27454910.

5: All Things Considered.  Colorado Gov. On How Federal Marijuana Decision Could Affect State.  January 4, 2018.



Graphics Credit:

1.  Photo at the top is a commercial cannabis grower from Shutterstock per their standard licensing agreement.

2.  Figure 1 above is reproduced with permission from [JAMA Intern Med. 2017. 178(4):569-572. doi: 10.1001/jamainternmed.2017.8298. Copyright©(2017) American Medical Association. All rights reserved." from reference number 1. License number 4335700705440.

American Academy of Sleep Medicine versus Minnesota Medical Cannabis Program

The American Academy of Sleep Medicine (AASM) came out with a position statement about the use of medical cannabis for obstructive sleep apnea (OSA).  In brief they think it is not a good idea.  The entire statement can be read at the link.  I think that it is important to keep in mind that they concerns about safety and efficacy are generally dependent on the fact that like most of the conditions on the Minnesota list,  there is minimal to no scientific data to back up the suggested uses.

The AASM is not the first professional society to take a position on medical cannabis.  One of the first purported applications of medical cannabis was for glaucoma.  The American Academy of Ophthalmology has a position statement on Cannabinoids for Glaucoma  that reviews the history of this application and concludes that although cannabinoids can lower intraocular pressure, the duration of this effect is too short and the side effect profile too problematic for cannabinoids to be used for this application.  The statement points out that long acting cannabinoids for this application were recommended by the Institute of Medicine in 1999, but as of 2018 statement - there has been not suitable cannabinoid derivative.

That brings me back to the familiar refrain on this blog and that is the fallacy that cannabinoids or any street drug for that matter represents some form of miracle drug. Humans have been aware of cannabis for many applications for about 5,000 years.  A reasonable question is why some miracle application or even one less than a miracle has not been found at this point in time.  Why for example, were opioids developed as effective pain medications from the natural compounds over the same period of time?  I have attended the lectures on physicians who advocate for medical cannabis.  Some of them invoke Chinese medicine and quasi-scientific explanations like the entourage effect  about why the whole plant needs to be smoked. I don't really see a need for physicians to certify people to access these largely unproven treatments, especially when medical colleagues are describing them as potentially unsafe and ineffective.

I have no problem with the state of Minnesota supplying medical cannabis to people with a condition that has no clear cut treatment. I have no concerns about the state supplying cannabis to people who are terminally ill.  I do have a problem when cannabis is listed as a treatment when in fact there is little to no evidence that it is effective and vastly superior treatments exist.  Glaucoma and obstructive sleep apnea are two of these conditions.  From a purely psychiatric standpoint post traumatic stress disorder, and autism have existing treatments and autism has a newly approved treatment.  In the case of Tourette's syndrome and other movement disorders - the data remains very preliminary.     

As a prescribing physician, I have serious doubts about the thinking that goes into prescribing cannabis as an actual medication.  I prescribe medications every day.  These medications are all approved for use by the FDA.  There are specific indications and off label uses. There are potentially serious side effects.  The medications have to be prescribed to take the patient's chronic illnesses into account.  For example, I would not prescribe a sedative to a patient who I thought might have obstructive sleep apnea.  Prescribing cannabis, even in a special program that eliminates smokable cannabis continues to not make any sense to me. 

The list at the top of this page is directly from the Minnesota Medical Cannabis program as of today.  It lists all of the current conditions that qualify a person to take it.  I see the list as a political compromise to delay and potentially thwart the recreational marijuana movement.  It should not be a surprise that medical cannabis has always been a mainstay of the strategy to legalize recreational marijuana.  While that drama plays out - I hope that people in Minnesota don't forgo effective medical treatment for medical cannabis.  Today that means CPAP for obstructive sleep apnea and glaucoma drugs and surgery for glaucoma.

There is no evidence that medical cannabis can come close to the medical effectiveness of those options. At the political level - this is also a great example of how politics negatively impacts quality medical care.


George Dawson, MD, DFAPA


References:

1:  Ramar K, Rosen IM, Kirsch DB, Chervin RD, Carden KA, Aurora RN, Kristo DA, Malhotra RK, Martin JL, Olson EJ, Rosen CL, Rowley JA; American Academy of Sleep Medicine Board of Directors. Medical cannabis and the treatment of obstructive sleep apnea: an American Academy of Sleep Medicine position statement. J Clin Sleep Med. 2018;14(4):679–681.

2:  Petitions to Add Qualifying Medical Conditions to the Medical Cannabis Program.  This document documents the review process for adding qualifying conditions to the list.  Link 



Graphic: 

The table at the top of this post is directly from the Minnesota Medical Cannabis web site and is used here as a public document.

First FDA Approved Cannabis Product - Epidiolex

Cannabidiol (CBD)

Headlines yesterday were that the FDA Peripheral and Central Nervous System Drugs Advisory Committee approved a cannabis product for the treatment of seizures.  The draft agenda for that meeting is available on the FDA web site but no vote or minutes of the meeting.  This has been a widely hyped application of medical cannabis since the term was first used to try to start the legalization of cannabis products.  Ironically the first example of a patient used as an example for this application did not have the syndrome in question.

At the  time I am typing this post there is no FDA approved package insert for the compound and no prescribing information available on the manufacturer's website.  There is a considerable amount of detail in the patent that is available online.  The patent focuses on the use of cannabidiol in treatment resistant epilepsy including Dravet syndrome; myoclonic absence seizures or febrile infection related epilepsy syndrome (FIRES). The patient states that when  cannabidiol is used for these disorders the total reduction in seizure frequency is 50-70% but as high as 90-100%.  The product is formulated to be used separately or with other anti-epileptic drugs (AED).  The patent suggests that the formulation is comprised of highly purified cannabidiol extract (98% w/w) with most of the psychoactive components - tetrahydrocannabinol (THC) removed.

The epidemiology and treatment of epilepsy especially Dravet's syndrome is reviewed in the patent.  It is clear from that data that there are no good treatments for these disorders and that conventional AEDs are partially effective at best.  The four treatment scenarios (non of which are randomized controlled clinical trials) all demonstrate efficacy for CBD in intractable epilepsy.  These results are included in the table below.

Trials	Treatment	General Response	Best Response
N=27 children and young adults Dx: severe childhood onset treatment resistant epilepsy (TRE)	Initial dose: CBD 5mg/kg/day titrated to a max of 25 mg/kg/day in addition to baseline AEDs	-after 3 months of therapy, 48% of patients had an equal to or greater than >50% reduction in seizures. -	- 2 patients were seizure free at three months - 6 patients had a 90% reduction in seizures at three months
N=9 children and young adults with treatment-resistant Dravet syndrome	- as above	- after 3 months of therapy, 56% of patients had an equal to or greater than 50% reduction in seizures,	- 2 patient were seizure free at three months -3 patients has a 90% reduction of seizures at three months
N=4 patients with myoclonic absence seizures who were taking at least two concomitant anti-epileptic drugs	-as above	after 3 months of therapy, 2 of the patients had an equal to or greater than 50% reduction in seizures, 1 patient (25%) had a 90% reduction at the three month stage.	-0 patients were  seizure free -1 patients with a 90% reduction of seizures at three months
N=3 patients with FIRES (febrile infection related epilepsy syndrome)	-as above	- 2/3 children has a 90% reduction in seizures	-2/3 children had a 90% reduction in seizures and regained some motor and intellectual functioning.

In these studies no patients were withdrawn because of side effects.  Common adverse events were somnolence, fatigue, decreased appetite, increased appetite and diarrhea.  Given the degree of polypharmacy it is probably difficult to determine what side effects are due to CBD and either the other compounds or interactions with the other compounds.   All patients had severe epilepsy with hundreds to thousands of seizures per month and in many cases required episodic aggressive treatment to stop status epilepticus.  In this population, placebo response would be expected to be very low.  The use of CBD in this population could easily be justified on a compassionate use basis because of illness severity and the lack of any severe complications from the CBD.  The results of these open label trials appear to be complied in reference 1.  Some of the authors have also published a review and  randomized, placebo controlled dose ranging study of the safety of CBD.  I cannot imagine that there was not an efficacy arm to that study.  There is also a 2017 commentary that looks at the general question about whether there is adequate evidence that CBD is effective for epilepsy(4).

A mysterious part of the patent process is that this is a simple organic chemistry extraction of CBD from cannabis plants and then resuspending for oral dosing.  The authors specify that THC is essentially removed.  The dosing is done in a standard mg/kg dose that would be expected for any medication. That dose range appears to be part of the patient. Does this patent mean that any CBD extracted from cannabis is the intellectual property of this company or is there more to it than that?  If that is the case then any product with a CBD/THC ratio could be patented and there are currently 11 of these compounds prepared by a similar extraction process in the Minnesota Medical Cannabis Program.  Is each one of these compounds patentable? Or is there some additional information about the formulation that is not included in the patent that would make this formulation more unique? At one point the patent states that the CBD can be synthesized as well as extracted.

The market for this product is potentially significant, if it works in less severe forms of epilepsy. Will it work for example in the case of a person who has a few seizures per month after their AEDs have been optimized?  Can that person take the necessary dose of CBD and not experience significant side effects?  Will the company or other companies try to get another FDA approved indication for CBD related products from the FDA? I suspect the standard will be higher in patients where there are compounds of equal or better efficacy.  Will physicians prescribe CBD derived drugs off-label to people requesting them for philosophical reasons (eg. I want to be treated with a substance derived from a botanical)?  Will the positive effects noted in these small trials persist as more and more people with epilepsy are exposed to the drug?  Will there be more significant side effects with post marketing surveillance and maintenance use? There are still a significant number of people who do not appear to respond very well to CBD.  Those are some of the questions I had considering the implications of this product release.

On theoretical grounds, a key question is whether the utility of this compound in severe epilepsy will lead to additional drug discovery of more compounds for this difficult to treat problem.  For now, the FDA has made a sound decision getting this compound into the hands of the physicians who treat these disorders on a day to day basis.


George Dawson, MD, DFAPA


References:


1:  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. Erratum in: Lancet Neurol. 2016 Apr;15(4):352. PubMed PMID: 26724101.

2:  O'Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav. 2017 May;70(Pt B):341-348. doi: 10.1016/j.yebeh.2016.11.012. Epub 2017 Feb 8. Review. PubMed PMID: 28188044.

3: Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood S, Morrison G, Sommerville K; GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018 Apr 3;90(14):e1204-e1211. doi: 10.1212/WNL.0000000000005254. Epub 2018 Mar 14. PubMedPMID: 29540584

4:  Perucca E. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? J Epilepsy Res. 2017 Dec 31;7(2):61-76. doi: 10.14581/jer.17012. eCollection 2017 Dec. Review. PubMed PMID: 29344464.

5:  FDA Briefing Document Peripheral and Central Nervous System Drugs Advisory Committee Meeting April 19, 2018 NDA 210365Cannabidiol

A Report From The Minnesota Medical Cannabis Program

I have described the Minnesota Medical Cannabis Program in a previous post.  It is a unique program because it does not provide smokable cannabis for medical purposes.  All of the cannabis is in a form that is vaporized, edible, absorbed through the oral mucosa, or transcutaneously after application to the skin.  It is produced by two companies and made into products of varying amounts of  tetrahydrocannabinol (THC), cannabidiol (CBD) .  In the original matrix from the first post there appeared to be a total of about 11 products based on the THC and CBD ratios. For the purpose of this report the cannabis products were classified base on ratios of cannabinoids and route of administration according to the following table:

The program came out with a report on the experience of patients with chronic intractable pain using the program this week.  They produce frequent reports and this is the latest. Although it is not a scientific study of the associated issues of pain relief it is interesting because of a number of considerations not the least of which is what happens when a state starts to manage a CSA Schedule 1 drug on their own and come up with their own process for certification and use.

The report details the cohort of patients who were qualified on the basis of intractable pain according to the following definition:  “pain whose cause cannot be removed and, according to generally accepted medical practice, the full range of pain management modalities appropriate for this patient has been used without adequate result or with intolerable side effects.” (p 4).

The report focused on the results and side effects of 2245 patients certified by various practitioners for intractable pain between August 1, 2016 and December 31, 2016. It contains basic demographics of the patients and practitioners as well as a breakdown of the possible origins of their chronic pain.  All of these details are available in the original report and I encourage any interested reader to find the details there.  I am interested in the type of medical cannabis being used and the outcomes.

These details are fairly interesting from a descriptive standpoint. For example, just using the product definitions there is a distribution of how the products are purchased.  The following bar graph illustrates the distribution of purchased products by THC and CBD content:

 
The report gets into more specific details about the types of THC and CBD products in each category and the average ingestion of these products per day in milligrams (mg). I am reproducing the first of a 4 page table here that contains progressively fewer patients in each strata:

It is apparent that very high THC products that are inhaled or ingested predominate the product distribution.  Although the largest single group of patients were averaging 81.5 mg/day THC and 0.6 mg/day CBD the range is significant from 4.4 to 553.8 mg/day THC and 12.2 to 1,439.2 mg/day CBD.

Patient and treatment providers were asked to rate their degree of benefit from the medical cannabis program on a Likert scale where 1 = no benefit and 7 - great deal of benefit.  Using that system 61% of the patients rated their experience as a 6 or 7 compared with 43% of the healthcare professionals rating the patient benefit as a 6 or 7.  Specific benefits were rated and the top three included pain relief (56%), sleep improvement (10%), and reduction in pain medications and side effects (7%). 

An area of interest in the report is whether or not the patient is reducing the amounts of other pain medications used in response to the use of medical cannabis. This question is asked to the certifying health care professionals.  For this report, 586 responses of a total of 692 were used to determine that pain medications were reduced in 58% of the cases and not reduced in 48% of the cases.  221 reduced an opioid with 127/221 reducing the opioid by 50% or more.  In addition, 16 reduced a benzodiazepine and 128 reduced a pain medication "other than an opioid or benzodiazepine" - but benzodiazepines are not pain medications.  The full list of medications reduced or discontinued are available in Appendix E.  Minnesota does have a Prescription Monitoring Program for controlled substances making it possible to quantify and confirm all of this data rather than depending on survey results.

The section of the report that I found most interesting was the section on a standard group of 8 symptoms followed in this patient group for improvement or no improvement.  These symptoms are listed in the tables below.

The response options are on a standard analogue scale where 10 is the worst possible symptom and 0 is the symptom is not present.  The report listed the results of this scale applied to intractable pain patients as shown in the table below.

It is an interesting report in that it gives improvements in symptoms over 4 months as well as the percentage of patients a 30% improvement in symptoms at some point in the initial 4 months, the percentage of patients who had a 30% symptoms improvement in the 4 month follow-up period, and the percentage of patients who had the 30% symptoms improvement and maintained it for at least 4 months.  Only 11% of the pain patients maintained a 30% improvement in pain symptoms over the 4 month follow up despite higher ratings of initial pain relief.  The most significant improvements were in nausea and vomiting.

Side effects were reported in the final section with about 10% of patient reporting severe side effects.  These side effects included somnolence, sedation, headaches, dizziness, lightheadedness, confusion, fatigue, abdominal pain, mental fogginess, inability to concentrate, anxiety, panic attacks, and insomnia.  Physical side effects were reported roughly twice as often as mental side effects and most were in the mild to moderate range.  A typical metric found in clinical trials - medication discontinuation because of side effects was apparently not determined.  In a series of statements included in the report, one patient stopped because of a lack of efficacy and there was a suggestion that stopping could occur for that reason or financial reasons but the data was not clear.

Although the current report is focused on intractable pain a couple of things seems clear.  First, these reports are not scientific.  There are no comparison drugs or placebos.  Medical cannabis is added in many cases to a combination of existing opioid pain medications and benzodiazepines.  In a purely qualitative sense, they do show what products are preferred by customers and these products contain significant amounts of THC.  Second, in the case of the 8 symptom rating pain relief from medical cannabis appears to be modest at best.  A significant number of patients acknowledged severe side effects, but were these side effects of the same level of severity that might be seen in a clinical trial?  In those patients who replaced opioids or to a lesser extent benzodiazepines - was that because the initial medications were ineffective for pain or because cannabis has superior effects on pain?

The most interesting part of the data to me is that fact that medical cannabis is highly promoted for chronic pain.  That promotion was initially political - for the purpose of legalizing medical cannabis.  Currently it takes the form of cannabis saving people from opioid overdoses and this report makes an attempt to record reduced amounts of opioids use due to the cannabis. The problem is that it is all survey data.  There are no standardized doses of cannabis and no attempt to determine a placebo effect.  Physicians used to reading clinical trials need to ask themselves: Is a patient interested in using medical cannabis in Minnesota capable of answering the questions in an unbiased manner?  Will their interest/belief in medical cannabis influence survey results? And if that is true - what does it mean that medical cannabis ends up with such a poor result for pain relief over a period of 4 months?  I have concerns about the survey results based on my interviews with thousands of cannabis smokers.  Although I am seeing people with significant addiction problems, I don't see the side effect frequency of insomnia, anxiety, panic, and paranoia that I am used to hearing hearing about.  And in this group, I can't help but wonder how many of them have significant addictions? I also don't see a discussion of the fact that many opioid users commonly switch to cannabis when the opioid supply runs low or they make an attempt to stop using. There are potentially several mechanisms occurring in this population in addition to pain relief and side effects.

Another issue indirectly addressed by this report is what happens when you do an end run around the FDA?  I have certainly been a critic of the FDA and its regulatory processes, but in the end there is always a study available for public discussion.  That study typically has much more information content about drug efficacy and tolerability than the current Minnesota study because of the scientific design.  This report is the type of data that you get when that regulatory hurdle is ignored.

The direction and legacy of medical cannabis in Minnesota seems to be contingent on the status of recreational cannabis.  The program has been criticized for being too expensive compared with smokable cannabis.  If Minnesota legalizes recreational cannabis, that may be the preferred route by many of the people in this program. Questions about the efficacy of cannabis in intractable pain remain unanswered despite all of the details in this report.



George Dawson, MD, DFAPA


References:

1:  Minnesota Department of Health Office of Medical Cannabis.  Intractable Pain Patients in the Minnesota Medical Cannabis Program: Experience of Enrollees During the First Five Months. Report

2: Desrosiers NA, Ramaekers JG, Chauchard E, Gorelick DA, Huestis MA. Smoked cannabis' psychomotor and neurocognitive effects in occasional and frequent smokers. J Anal Toxicol. 2015 May;39(4):251-61. doi: 10.1093/jat/bkv012. Epub 2015 Mar 4. PubMed PMID: 25745105.


Graphics:

All tables excerpted from reference 1 as a public document with no copyright.

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.