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

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.