Dr Graham Associate Professor Gulbransen David Caldicott General Practitioner Emergency Physician Kingsland Family Health Centre Calvary Hospital Auckland Clinical Lead Australian Drug Observatory
8:30 - 10:30 WS #1: Medicinal Cannabis Workshop 11:00 - 13:00 WS #8: Medicinal Cannabis Workshop (Repeated) Medical Cannabis- A Primer for Clinicians
Associate Professor David Caldicott B.Sc (Hons), MBBS(Lond.), FRCEM, Dip.Med.Tox
australian medical cannabis observatory The Australian Medical Cannabis Course
Associate Professor David Caldicott B.Sc (Hons), MBBS(Lond.), FRCEM, Dip.Med.Tox
australian medical cannabis observatory Who the hell are you?
“Jack of All Trades…” “Plant for All Seasons…” Beginnings…
australian medical cannabis observatory Beginnings… Beginnings…
No financial disclosures, associations or political affiliations “Why not…?”
Lachenmeier DW, Rehm J. Comparative risk assessment of alcohol, tobacco, cannabis and australian other illicit drugs using the margin of exposure approach. Sci Rep. 2015 Jan 30;5:8126. medical cannabis observatory So I went looking… Lesson 1 I needed to learn more, because I was taught nothing real on this subject in medical school australian medical cannabis observatory Lesson 2 There is already an awful lot already known about using cannabis for medical purpose
(just not by doctors) australian medical cannabis observatory ‘Where’s the evidence…?’ Practice Guidelines
Systematic Review / Meta-analysis
Randomized Controlled Trial
Controlled clinical study
Retrospective / Prospective Cohort Study
Case Reports / Case Series
Expert Opinions The Historical Human Experience This is not an academic ‘Terra nullius’
John Boyd Macdonald Lesson 3 There really does seem to be some benefits associated with medicinal cannabis
australian medical cannabis observatory Lesson 4 There could also be harms associated with medicinal cannabis
australian medical cannabis observatory Lesson 5 Regardless of benefits or risks, patients see it as a way of taking control of their conditions australian medical cannabis observatory The Machine vs The Garden “Slow Medicine”
australian medical cannabis “content, context, and community” observatory
2 major camps
Cannabis Cannabis is Is great Dangerous- for Much more everyone, Us Work Needs always- To Be now. done
australian medical cannabis observatory Interpreter Diffusion of Innovation
Adoption Profile Innovators Early Early Majority Late Majority Laggards Adopters Conservatives Psychographic Technologists Visionaries Pragmatists Skeptics
Critics & Joiners & Social Inactives Technographic Creators Collectors Spectators
After Cialdini, Everett Rogers, Forresters, and Moore & Gladwell Diffusion of Innovation
C T h h a e s Adoption Profile Innovators Early Early Majority Late Majority Laggards Adopters Pragmatists Conservatives Skeptics Psychographic Technologists Visionaries m Critics & Joiners & Social Inactives Technographic Creators Collectors Spectators
After Cialdini, Everett Rogers, Forresters, and Moore & Gladwell • Globally, ongoing debate surrounding – Legalisation – Decriminalisation
• Borrowing a term from Israeli approach, we support the… Medicalization of Cannabis Medicalization of Cannabis
• Appropriate approach for doctors
• Medicalization of Cannabis – Development of indications and practice – Standardization of product • Cultivation • Compounding • Distribution australian • Delivery medical cannabis observatory Mandatory Disclaimer • Course is for educational purposes
• Does not constitute medical advice for any specific medical case, condition or patient
australian medical cannabis observatory Today, we’re going to touch on…
• A bit of History…
• A bit of Science…
• A bit of Medicine… australian medical cannabis observatory A Little Bit of History…
How did we get here?
australian medical cannabis observatory Medical Cannabis- Ancient History • Probably originated in Central Asia
• Use predates writing in human evolution
Trade routes of broad leaf drug variety throughout the Central Asian region. Medical Cannabis- Ancient History
• Hemp was one of the first plants ever cultivated
• Extensively used for food and fibre
• Probably quickly followed by medicinal use
Çatalhöyük, 8000BC australian medical http://www.catalhoyuk.com/ cannabis observatory Medical Cannabis- Ancient History
Ancient Chinese had their own symbol
‘da ma’
australian medical cannabis observatory Medical Cannabis- Ancient History
• The Ramesseum III Papyrus (1700 BC)
• Eber's Papyrus (1600 BC)
Hieroglyphs Demotic • The Berlin Papyrus (1300 BC) "Shm-Shm-Tu" or "sm-sm-t” "The Medical Marihuana Plant” • The Chester Beatty VI Papyrus (1300 BC) australian medical "An Ancient Egyptian Herbal” By Lise Manniche, cannabis British Museum of London / University of Texas 2006. observatory Medical Cannabis- Colonial History
• British Empire ran a very successful colonial distribution • Hemp was at heart of British naval power, in the Age of Sail. • Every first rate man-of-war in British navy needed 60 tons of hemp for – Sails – Uniforms Took 140 hectares of – oakum Cannabis spp. to – rope produce this amount! Medical Cannabis- Colonial History
• Americas – George Washington
– Thomas Jefferson
australian medical cannabis observatory Medical Cannabis- Colonial History
• Australia
• More ‘cannabis colony’ than ‘prison colony’
• Came on First fleet Medical Cannabis- Colonial History
“From a pint of hemp-seed, sent from India in 1802, I have now sown 10 acres for Government.”
Seems to have grown quite a THC rich strain…
Phillip Gidley King “Trying to make rope out of dope” 3rd Governor of Australia The Origins of Medical Cannabis
Enter the Irishman… – Irish physician – Polymath • used IV fluids for cholera • helped roll out telegraph in India – First to systematically report on the medical use of cannabis in India – ? treated Queen Victoria’s dysmenorrhoea
William Brooke O’Shaughnessy 1809-1889 On The Preparation of Indian Hemp Cannabis Indica in 1839 of Medicinal Cannabis
australian medical cannabis observatory of Medicinal Cannabis (1840-1937)
australian medical cannabis observatory William Osler
• acknowledged father of modern medicine
• stated of migraine treatment: "Cannabis indica is probably the most satisfactory remedy. Seguin recommends a prolonged course."
• This statement supports its use for both acute and prophylactic treatment of migraine.
Osler, W. and McCrae, T., The Principles and Practice of Medicine, Appleton and Co., New York and London, 1915, 1225 pp. Indian Hemp Drugs Commission Report 1894 • 3,281-page, seven-volume report on the marijuana ‘problem’ in India by the British concluded: • "Viewing the subject generally, it may be added that moderate use of these drugs is the rule, and that the excessive use is comparatively exceptional. The moderate use produces practically no ill effects." Nothing of significance in the report's conclusions has been proven wrong in the intervening century.” Cannadonna cigarettes
Age (Melbourne, Vic. : 1854 - 1954), australian medical Monday 5 March 1928, page 5 cannabis observatory Cigares de Joy From The Chronicle SA, Thursday 29th March, 1934, Pg 56 The Origins Of Medical Cannabis
• The Fall from Grace – Did it fall…? • Patent medicine industry? • Development of better alternatives?
australian medical cannabis observatory The Origins Of Medical Cannabis
• The Fall from Grace – Did it fall…? • Patent medicine industry? • Development of better alternatives?
– Or was is it pushed…? australian • Anslinger medical cannabis observatory Patent medicines • Aka ‘nostrums’ • proprietary medicine made and marketed under a patent and available without prescription Not all candy sprinkles…
australian medical cannabis observatory Smith's Weekly, Saturday 27 May, 1922 p 12 Questions were being asked… • variability in its effects among patients • variability among different preparations of cannabis • pharmacologically ‘active principles’ – not known – not quantified
• Importantly, safety was never a matter of discussion – never been a case of poisoning recorded from medicinal use
Kynett, H., ed. (1895) Cannabis indica. Medical and Surgical Reporter (New York), 72, 1895, 562. The Pure Food and Drug Act of 1906
• regulated the labeling of medical preparations containing Cannabis, for the first time
australian medical cannabis observatory Harry J Anslinger Commissioner of Federal Bureau of Narcotics (1930-1962)
australian medical cannabis observatory Harry J. Anslinger "There are 100,000 total marijuana smokers in the US, and most are Negroes, Hispanics, Filipinos and entertainers. Their Satanic music, jazz and swing, result from marijuana usage. “
australian medical cannabis observatory Harry J. Anslinger
“This marijuana causes white women to seek sexual relations with Negroes, entertainers and any others.”
“ Reefers make darkies think they are good as white men" Marihuana Tax Act (1937)
• Introduced at specific request Harry Anslinger
• prescribed the payment of a US$1 tax for each business deal regarding Cannabis for medical or industrial use and of
• US$100 for all the other purposes,
• Incidentally, this was effectively the start of Prohibition V2
australian medical cannabis observatory Musto, D.F. (1972) The Marihuana Tax Act of 1937. Arch. Gen. Psychiatry 26, 101–108 Marihuana Tax Act (1937)
• law did not forbid the use of Cannabis, but.. – purchase was so expensive – violations to the rules so punitive, with fines up to US$2000 or even 5-year imprisonment
• all research / use about the medical use of Cannabis was discontinued. australian medical cannabis observatory Medical Opposition
• Strongly opposed by American Medical Association through Dr William Woodward was firmly contrary to such policy
• continuing to assert the pharmacological potential of this plant in numerous pathological conditions, despite its adverse psychotropic effects. australian medical cannabis observatory MDroketchcs : More Laughs : More Short Stories track&j&cK MOUTH ORGANS JL WEST INDIAN
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:i'.- : ! New Drug That Maddens Victims Drugged Cigarettes: G-Man Warns Imported General ONLY OUR OWN! I PLANT GROWS WILD IN QUEENSLAND \ [?] Australia STIR WARNING IN FROM FIRST DOPED ARMY AMERICA PACKETS by "Smith's ' Weekly" in all Aus tralian capitals show that MEXICAN drug that INQUIRIESdiscontent is widespread SNEAKED IN regarding the proposed drives men and women SIR HARRY CHAUVEL Aus to of an English appointment tralian, and one of the many the the wildest excesses army officer to position of brilliant military leaders whom J has FEW mari of the Aus this country produced during cigarettes containing Inspector-General last and at made its Men oT the the war, can, need, first appearance in — tralian forces. future war. causes produce in any huana the drug which its A.I. F., 'militia-men, and officers, Australia. including those of senior victims to behave like raving sex rank, are all strongly hostile, It distorts moral values and leads to degra A A. M. BANGS, who heads the U.S. Na rcotics Bureau in ALL GAOL: orgy was Hawaii, examining IN Their wild shattered when and Diggers at various meet maniacs, and has made pathetic sexual marihuana cigarettes seized in a recent Honolulu raid. Note how the cig Federal raiders burst in on the wild in Hono in Melbourne are knov/n. ding extravagances. — party recently ings slaves ot thousands ot arettes and young Americans are packed transported m tins of regularly marketed cigarettes. lulu. Official photo of the men dnd women caught in a G-man .to have expressed liveliest It is called marihuana!. dragnet at a marihuana party. Dazed, stupid, the next day , opposition. have been smoked at recent in Marihuana is obtained from a plant ' parties Sydney. they could hot tell a coherent story of what had happened. All are 14 V>NE 'highly-placed officer ex- in gaol for terms of from four to months. the (Cannabis sativa) thai has been discovered vj? plains that hostiUty on flHT They had been smuggled in on ships from officers is stifled bv the grbwing wild iti of the coastal part of, many parts America. hush-hush by the policy adopted' of Queensland . Defence ARMS TRAFFIC Department. The chief of the U.S. in Honolulu, wants distinction drug squad name of Hie projected ap- Unless Queensland the rp'HE an at 7" pointee has not yet beeri [?] of Australia's front door, said to 'Smith's Week the State to let loose bn Australia nounced, hut assumnbly there are AUSTRALIA'S peace plans being there : ... only two classes of Imperial Army; described some ly's" special representative l.: are going great gunsi vj. by authorities as ofilc-irs. ;.'from 'Which- to choose; There are those who have received honor — more or LYONS word of Anzac. than cocaine mor STILL demoralising if prompt action is not official approval by having been QUIl "Undoubtedly, '-the it its officials now given recent appointments, hy ' phine, should send out ll?XTR'A taxation will: be de- taken, marihuana will flood Australia and War Office, which, they could hardly., oyer to who; - discover how far the Cannabis resign at present, and those ; tence.,, , ...... plant, New Zealand by way of the many trans- liy having failed to receive any ap Australian has and New Zealand j sativa, spread. " pointment, have been tacitly re . / Pacific and IGNORES Army, Cordial! , passenger ships freighters the War Office. Australia jected by, Should addiction to this once does not want a War Of M-B.D I T-HOORAY-NEAN Peate , , drug get a certainly ' to fice . . Pact! hold in weeks ago, the Narcotics Squad in Honolulu, reject. ; the as it has Commonwealth, already "Smith's drew "Smith's" special representative in campaign. Weekly" jAT-MORE-EGGS ,sug- in will an Hawaii. Hot Resentment . Producers on a America, there be almost unlimited attention to the fact gested. " will be "We plan to smash this racket on THE the FACTS good lay. ; to that hemp plant American soil, and the Australian In according to the Aus supply available its devotees and to those any case, the authorities will receive all our co tralian officer in question, experi jJONKEY EN-glands for Mussolini! who will SEVEN(Cannabis sativa) , inevitably make a business of it in dried leaves of which operation in beating it at their end." ence shows that the English general W" NDER the Government our defence Another high who is Lyons pro is incurably conservative, and could in Spain it in its are smoked as mari official, RMISTICE expected. providing prepared form. the trans-Pacific not quickly, if indeed at all, adant But wild in watching ships, I gramme threatens to beget within our is Spain sufficiently armed huana, was growing suggested that Australia should himself to our- conditions, especially for peace? the action of parts of Australia. send an officer to Honolulu to boundaries an enemy as ruthless as in relation to the human element; recently that its use has be study J any claims to have seen a — the racket in operation and the The discipline and temperament JJOTORIST Althoughmarihuana the name come in the This week it was revealed in invader could be. on a Victorian Coun widespread methods by which America is at A. of the Australian civilian ; soldier leopard that M. BANGS, U.S. Narcotics Bureau chief, in Hawaii, with sample of marihuana bushes We'll believe we given to the dried and pow United States. Sydney cigarettes 'contain tacking it. are different from what he try road. it when found in an old Chinese in the heart of Honolulu. totally see the vile weed were cemetery, right The racketeers used faces a Frankenstein of its has known. a motorist's wife wearing a dered leaves mixed with a ing being The files of the United States Already England previously Both these and other bushes as supply bases. leopard skin coat. botanically and chemically smuggled into Australia Narcotics Bureau reveal the alarm own It is understood that the Federal small of tobacco Cannabis by making in the private armaments ring. The proportion sativa is closely allied to members of the extent to which the drug has Cabinet has only one .re children's electric crews of vessels ing placed jJANY ' toys — has been Cannabis indica. from which Indian the Hawaiian Islands. of the monster threatens to Britain striction on the Recommendations Caution needed in known for many from the United States gripped rapacity cripple dangerous. ' hemp or hashish, well-known for trading to made G-men and Customs searchers be by the proposed ap the ohm.? years in Mexico, it is only its violently sex-stimulating and Honolulu. while pretending to defend her externally. effects, have made internally pointee. He must. not advocate is prepared, with, the difference ntany successful raids At two Because the racketeers armaments conscription. that the action of G. sativa is Darlinghurst parties, recently. This week's cables report that rings and times more stewards and the forlorn addicts violate re In favor of the appointment, twenty potent than ship produced packets combines have become that the War is that of C. indica. of American cently legislated Federal laws, all so organised it is asserted that modern devel husband is jealous of poor little Tootums!" cigarettes, which "My terribly the arrested persons — mostly young armaments have Under the influence contained marihuana. — the Air and the Minister for Co-ordi opments in of the men and women have been clapped Ministry, Ministry, newer the addict becomes made our military . technique drug, These and the into gaol. nation of all find themselves at limes almost an cigarettes, llttteilllMMtt Defence, helpless, compelled uncontrol obsolete, but Australia for years drunk the On Customs officers at lable sex-maniac, able to obtain Continued From Column 4 cheap liquor by April 30, to extortionate for defence tenders London a Honolulu pay prices obviously has supported in satisfaction only from the most guests, caused scenes of revolt made the largest haul of marihuana in local Twelve — military . and a navy; liaison appalling of perversions and sex history. rigged- compelled, in short, to surrender the country to ing extravagance. pounds of the were all orgies. Its effect is the same on infamous weed CRICKET on the Hearthr—from the A.B.C. officer, to keep us abreast of Liners will armaments traffic. either sex. and freighters which cross found in the possession of room the of the private new defence developments. the Pacific from America to Auck stewards on the U.S.S. "Republic," The full extent of the inroads QEVENTEEN- YEAR - OLD treaties make TUORKING on "Kakariki." Resentment is serious enough. land (N.Z.), Sydney, and Melbourne, America's largest army English JfyfODERN splendid sunken Week after week "Smith's has warned the which marihuana-smoking has New Traffic! transport, down £80 a Weekly" Prevent girl turns week for diver meets shark in Drug hundreds of men in which cruises between New York confetti. dining- But a is the in carry young greater danger made in the United States was Unlike divas meet Government of this menace. their crews. and Honolulu by way of singing. Hollywood room. He's not the only one to Lyons very evitable delay in our defence brought home to the authorities few miles of where the lately become one of Panama, turn ... for the CountI While a certain amount of control Brisbane, Caloundra, a hotbed of vice and rackets. who down singing for £80 a 0UT. shark in the dining-room. only recently. most For these footloose men drug ; A preparations. It would take can be exercised over cocaine and long-leafed plant, Cannabis sativa, Brisbane's fashionable holiday years week. century of world-wide experience has shown that, It was discovered a num and it grows in in have been smuggling ashore silk Continually, marihuana dens in A/TR, CASEY says he is satisfied months before even a super- that morphine, inasmuch as the source is to be seen and in resorts, profusion defence problem": the of ber growing freely stockings, lingerie, shoes, Honolulu are cracked with National Insurance "ENGLAND'S jin sphere armaments manufacture, private genius could adequately report of sex-crimes in. the Eastern of neither drugs is to be found parts of Moreton and „ Stradbroke swimming being open ALL the Powers are going great plan. Bradman and Co. tlie districts farther north it liter the latest "hot" upon shore fortifications, aero Stales had been committed by within the country and that tech Islands. suits, music, tobacco, by raiding, squads. . in the cause of Peace. This disposes of the criticism that it . enterprise cannot be trusted, that it develops a traffic and other guns dromes, troops, marihuana addicts and that a nical skill is to extract ally flourishes in many places.' things which fascinate transport, guns, required For the same reason tha . the The drugged victims are like pleases nobody. CURTIN condemns insurance worse than war because it not only drives nations into and munitions. series of University and either from their and delight their Australian and that a woman will soon MR\ High plants, practically United States Government is now punch-drunk fighters. They cannot JJUMORED bill. Seems to a Curtin School scandals in California in no can on mari New Zealand friends. be able to him Hitler. constructing bomb be . eventual with all attendant but meanwhile Is Parliament justified in pass control be kept spending thousands of dollars try be questioned for hours, sometimes call Her "LONDON war, horrors, which both niale and female huana. This. new can be Acres It! proof shelters to house thou raiser. . ing any Defence estimates mean drug pro Of ing to stamp "out the smoking of Now, some of them ,are bringing days. those nations and students had participated had cured from a shrub which grows Load Ship At Darwin." sands of people in event of air cripples politically economically. time? - marihuana, the Queensland Govern in. the marihuana cigarette, which "ROOPS not had their origin in marihuana main Not The women sit on their cell-cots, Hope that's all ever have raids." . Masses in de col' col' QR. Dr-ought. freely alongside roads and in far from Flying Fish Point, ment, which possesses direct con can easily be smuggled in a case they . : To our armaments over to enter The Minister is reported to parties. . no more their faces and clothes ripped, try to load. give making private backyards. It requires six miles from Innisfail and situ trol over all noxious- plants within with other cigarettes, in the cuffs groun'l have stated that the new ap ing to piece together what did 250.000 tons of is to Australia over the death-traffic. The Californian denouement preparation than the simple drying the State, should take to of inside and in they to, buy prise give to pointee would "by direct contact ated at the mouth of . the Johnstone precautions trousers, hats, a in their of lust. to seek indemnities from tj.M.A. can't swallow the Medical gRITAIN . came when two girls, one of the leaves and the rubbing of ensure that it never gets hold here. thousand other orgy meat. Bully us? with the Minister for Defence, aged a p simple ways. "JAPAN Practitioners' Pill. ,for twenty, and the other them between the palms before they River, is patch of it which covers The men come out Canton." Way the Chinese steal and his Cabinet have moved toward the in eighteen, Because of its slowly of the Lyons already keep the Government fully committed suicide after one are mixed with tobacco and made five or six acres, the accessibility and The cigarettes are coming from bombs dropped from Japanese air teachers from Austria." That's of farther along that gave them frenzied will be carried "jgKI establishment of this evil within the Commonwealth. formed of the state of the mili these in which into plentifulness, mere prohibition Honolulu. stupor craft is terrible. JPOLDING go-carts orgies they, had cigarettes. coast, near Babinda. it is" to be seen something /where they've been tary defences." against it and fines for smoking it sexual desires and colossal physical only during certain' hours on recently member of that member of that taken part. "Smith's" first appeal to Austra Every Cabinet, every So far, marihuana is hardly in, plenty— also around Trinity Bay will have not the slightest effect. P-revalent! Victorian railways. Next they'll skating on thin ice. If he is not kept informed To-day the United States Gov lian authorities to take action strength. g-TILL be held for the known in Australia. But in Sydney and near Port early decide to carry babies. Government, must personally responsible ernment is so alive to Douglas. There is only one of dealing the marihuana only folding now, whose fault is it? fully the it has been smuggled ; ashore way against menace ias Read what was recently reported bulls killed in is sure to make Us sit such Much farther south, around Mont- with the curse, and that 'fighting INGLAND manifold which must follow a step. seriousness of marihuana that now and then members of the marihuana; won wide applause from the special Mr. H. J. United "gPANISH A-T Pluvius misery AND BY WHAT PROCESS OF by it with more or less is the most by Anslinger, aerial bombardment." Abora- last Jupiter has come up when it comes to a Test. it has created a force crews ville, grows by application of the of G-men as LOGIC THE MINISTER special of American vessels., These squad Washington to earth. HAS within freedom, its deadly qualities com drastic for the States Commissioner of Narcotics,, binabull. down Before it is too late, the present policy of private the Federal Investigation are the, only cases on record of its penalties possession signed to smash the vicious racket BEEN INVOLVING AUSTRA Bureau to deal with it. pletely those who of the dried leaves, lest this country, who drive garden to honor famous use here. We should make sure that unsuspected by in Hawaii, a stone's throw from Aus heads the national STATED that the New Zealand fflSTORlC armaments traffic must be reversed. LIA IN AN EXPENDITURE OF see it it M-e A-lone. What has home to it there every day and know by having checked the cocaine and tralia's front door. g-ENEFIT Australians sought for Canberra; MILLIONS. WHEN ON HIS brought are,, no, niore- one or against marihuana: tuatara is the most primitive of ' the other of the vernacular morphine habits, finds that it' has As in so in armaments manufae HE "NOT "Why didn't you stop when you saw my hand raised?" the full force of the menace is most STREETS are useful for Dad now has a name for So long as it isn't full of blooming France, Australia, OWN ADMISSIONS IS " There are places on the Queens names which it possesses. Its oc acquired another equally as bad and "The warning is timely," teaching reptiles. 1 Me come froma dis ! this: land some of a Mr. Anker M. chief of KP" Please turn to Page 2. the idea how to scoot. the ture must be a Government FULLY INFORMED"? "Excuse, pliz just Italy morning coast, them within currence has been reported from infinitely more difficult to suppi iss« said Bangs, young city agent. politicians. activity.
, ; freshness Ijj||For coos 0 AVFW "Si HHland smoothness give me..VJrerlLw 50 for 39 ||H ' 1 . .. , v : .r
National Library of Australia http://nla.gov.au/nla.news-page25337996 National Library of Australia http://nla.gov.au/nla.news-page25338168 The Marihuana Problem in the City of New York, Mayor's Committee on Marihuana, New York Academy of Medicine, 1944 • "The practice of smoking marihuana does not lead to addiction in the medical sense of the word.”
• "The use of marihuana does not lead to morphine or heroin or cocaine addiction, and no effort is made to create a market for those narcotics by stimulating the practice of marihuana smoking.”
• "The publicity concerning the catastrophic effects of marihuana smoking in New York City is unfounded." australian medical cannabis observatory Death blows…
• 1941, Cannabis was removed by the United States Pharmacopeia and from the National Formulary
• 1944-45 as part of vindictive campaign by Anslinger – forced the American Medical Association to deny the La Guardia report and – declared forbidden every study on Cannabis medical use.
• 1960s, due to the popularization of Cannabis for recreational purposes, it was definitively classified as a substance of abuse. australian medical cannabis observatory • Why don’t we have more compelling evidence than this about the therapeutic use of cannabis? “As the National Institute on Drug Abuse, our focus is primarily on the negative consequences of marijuana use. We generally do not fund research focused on the potential beneficial medical effects of marijuana.” Shirley Simson, NIDA New York Times, 2010 The Re-Medicalisation of Cannabis
• Globally, ongoing
• Greatest effects following changes in USA
australian medical cannabis observatory Current as of 2017 Predicted Value of US market Predicted Value of US market Global Medicinal Cannabis Law, 2018
Legal Decriminalized
Illegal but uninforced
Illegal No Information australian medical cannabis observatory A Little Bit of Physiology…
The Endocannabinoid System
australian medical cannabis observatory The Endocannabinoid System…?
• There IS an endogenous cannabinoid system- aka ‘endocannabinoid system’ (ECS)
• It’s important- probably really important
• So, why am I only hearing about this now…?
australian medical cannabis observatory The Endocannabinoid System…?
• Only relatively recently described
• Research has been discouraged
• Just not taught in medical school australian medical cannabis observatory The Endorphin System vs The Endocannabinoid System
1976 4000 BC 1801 Endogenous opioids Sumerians morphine isolated 1973 (enkephalins, endorphins) described opiates from opium opioid receptor Endorphin System BCE / ACE Endocannabinoid System 2000 BC 1964 1988 1992 Chinese THC cannabinoid endogenous described cannabis isolated receptor cannabinoids from cannabis (anandamide, 2-AG) australian medical cannabis observatory Cannabinoid Publications
800 “Medical (cannabis OR marijuana)” 700 600 500 400 300 200 100
0
1967 1978 1989 2000 1951 1952 1954 1964 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 australian medical cannabis observatory “As the National Institute on Drug Abuse, our focus is primarily on the negative consequences of marijuana use. We generally do not fund research focused on the potential beneficial medical effects of marijuana.” Shirley Simson, NIDA New York Times, 2010
australian medical cannabis observatory The Endocannabinoid System in Nature
• Extensive distribution
• Old- VERY old – ?600 million years ago
• Highly conserved
australian medical • Suggests significant functional purpose, cannabis across species observatory The CB receptor gene tree with supplemental data (A), mirrored by a phylogenetic tree of major taxonomic clades (B
• CB receptors present in vertebrates as well as very primitive metazoans (Hydra vulgaris)
• CB gene must have evolved prior to divergence of these organisms’ ancestors
• happened at > 600 million years ago australian medical McPartland & Pruitt Sourcing the Code: Searching for the Evolutionary Origins of Cannabinoid cannabis Receptors, Vanilloid Receptors, and AnandamideJournal of Cannabis Therapeutics, Vol. 2(1) 2002 observatory The Endocannabinoid System in Nature
• So, significant functional purpose – but what…?
australian medical cannabis observatory The Endocannabinoid System in Nature
• So, significant functional purpose – but what…?
“homeostatic regulatory system, influencing multiple physiological processes”
australian medical cannabis observatory The Endocannabinoid System in Nature
• Like what?
australian medical cannabis observatory The Endocannabinoid System in Nature
• Like what? • modulation of pain • seizure threshold • appetite • digestion • mood australian medical cannabis observatory The Endocannabinoid System in Nature
• The ECS may also play a role in regulation of • immune system • tumour surveillance • fertility • bone physiology • hypothalamic-pituitary-adrenal axis • intraocular pressure australian medical cannabis observatory
‘The Endocannabidome’
australian medical cannabis Solymosi & Köfalvi Cannabis: A Treasure Trove or Pandora's Box? observatory Mini-Reviews in Medicinal Chemistry, 2017, 17, The Components of the Endocannabinoid System • The basics are the same as any homeostatic feedback system…
– Receptors
– Ligands
australian medical – Modulators cannabis observatory The Components of the Endocannabinoid System • Also some additional elements that create a extraordinary diversity and subtlety of response
australian medical cannabis observatory The Components of the Endocannabinoid System • The basics are the same as any homeostatic feedback
Ligand binds to system membrane receptor
– Receptors
– Ligands Ligand–receptor complex Triggers intracellular response australian medical – Modulators cannabis observatory Cannabinoid Receptors • Before the discovery of receptors, action of THC thought to be similar to that of alcohol – Cell membrane “perturbation”
australian medical cannabis observatory The Endocannabinoid Receptors
• 2 main receptors
• CBR1 & CBR2 • Very similar in structure • G proteins
CBR1 (472 aa) • 7 transmembrane australian elements medical cannabis observatory The Endocannabinoid Receptors
• 2 main receptors
• CBR1 & CBR2 • Very similar in structure • G proteins
CBR1 (472 aa)
CBR (360 aa) • 7 transmembrane 2 australian elements medical cannabis observatory The Endocannabinoid Receptors
• CB1 • Cloned in 1990
CB1 Receptor 1. Cortex • Located mostly in CNS 2. Basal ganglia, Caudate nucleus & Putamen • The most widely expressed G- 3. Hypothalamus 4. Cerebellum proteins in the brain 5. Hippocampus 6. Amygdala • 10x the number of opiate 7. Spinal Cord receptors CB2 Receptor 1. Glial cells
• Also expressed peripherally australian medical cannabis observatory
Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990 Aug 9;346(6284):561-4. Downloaded from jnm.snmjournals.org by on July 5, 2014. For personal use only.
with the distribution of CB1 receptors (17), which de- creased slowly over time. Radioactivity in the brain peaked by approximately 30 min and was approximately 3.2 SUV for all areas of the neocortex (Figs. 2 and 3A). Areas with high CB1 receptor density (e.g., putamen) had an even greater concentration of radioactivity, peaking over 4.0 SUV in most subjects. Radioactivity in the brain decreased slowly, remaining within approximately 85% of the peak by 2 h and within approximately 60% of the peak by 5 h. We averaged radioactivity concentration from 20 to 60 min after injection to represent brain uptake (brain uptake20–60; Supplemental Table 3). Two regions of the brain consistently demonstrated less uptake of radioactivity than other regions. The first region, pons, had a peak SUV of approximately 2.4 within 8 min. After the peak, washout of radioactivity from the pons was 1.5–2 times faster than from other regions at 60–120 min after injection. The second region, white matter, typically peaked at an SUV of approximately 1.2 about 15 min after injection and remained nearly constant until the end of the scan, with minimal washout of radioactivity. The skull had a significant uptake of radioactivity, which could reflect bone or marrow (Fig. 3B). Among regions of the skull, the clivus, which contains significant amounts of marrow, had the greatest uptake of radioactivity, suggesting 18 that marrow more avidly takes up F-FMPEP-d2 or its 18 radiometabolites. FIGURE 3. Time–activity curves of F-FMPEP-d2 in brain from single subject scanned for 300 min. (A) Decay- corrected measurements from putamen (n), prefrontal cortex Plasma Analysis (h ), cerebellum (d , pons (s ), and white matter (· ) were fitted 18 with unconstrained 2-tissue-compartment model (–). Puta- The concentration of F-FMPEP-d2 in arterial plasma peaked at 1–2 min and then rapidly declined because of men was consistently region of highest brain uptake. White matter was consistently region of lowest brain uptake, CB Receptor Distribution in Humanfollowed CNSby pons. (B) Decay-corrected measurements from 1 same subject demonstrate uptake of radioactivity in clivus (¤ ), occiput () ), and parietal bones (: ). Concentration (Conc) is expressed as SUV, which normalizes for injected activity and body weight.
distribution in the body, followed by a slow terminal phase of elimination. To quantify the exposure of the brain to 18F- 18 FMPEP-d2, we fitted the concentration of F-FMPEP-d2 after its peak to a triexponential curve (Fig. 4A). Of the 3 associated half-lives, the first 2 (; 0.4 and 5.7 min) largely reflected distribution and the last (; 82 min) reflected elimination (i.e., metabolism and excretion). However, the 3 components accounted for nearly equal portions of the total AUC0-N : approximately 18%, 28%, and 33%. The portion before the peak accounted for approximately 20% 18 of the AUC0-N . The concentration of F-FMPEP-d2 in the plasma of some subjects remained the same or slightly increased during the 2 later imaging intervals (150–180 and 18 FIGURE 2. F-FMPEP-(Terry,d2 in 2010)human brain. PET images 210–240 min) but declined during the rest intervals (120– 18 from 30 to 60 min after injection of F-FMPEP-d2 were 150, 180–210, and 240–270 min). During the rest intervals, averaged (left column) and coregistered to subject’s MR subjects arose from the camera and walked around, images (middle column). PET and MR images are overlaid in suggesting that the shifting of fluid in the body may have right column. 18 mobilized and redistributed F-FMPEP-d2.
18 IMAGING CB1 RECEPTORS USING F-FMPEP-d2 • Terry et al. 115 The Endocannabinoid Receptors
• CB2 • Located mostly in
CB2 Receptor immune system 1. Spleen 2. Bones 3. Skin 4. Bone Marrow • Also peripheral nerve 5. Liver 6. Pancreas terminals • Up-regulated on other tissue, under stress
Nature 365, 61 - 65 (02 September 1993); doi:10.1038/365061a0 Molecular characterization of a peripheral receptor for cannabinoids Sean Munro, Kerrie L. Thomas & Muna Abu-Shaar CB2 receptors • expressed on the cell membranes of B cells, T cells and macrophages.
• CB2 receptors are generally inhibitory to immune cell activation. • Expression is inducible • number of receptors is increased by inflammation.
• in mice, reduced CB2 receptor signalling results in increased severity of inflammation in multiple organs, including the brain and the liver. CB2 Receptor Distribution
(Ahmad, 2013) Cannabinoid Receptors • Q: How do we work out the function of these receptors? Cannabinoid Receptors • Q: How do we work out the function of these receptors?
• A: See what happens in mice that have each of them ‘bred out’- ‘knockout mice’ Cannabinoid Receptors • But wait- there’s more…
– CB1 and CB2 knockout-mice crossbred to create mice that had neither receptor. – “double knockout mice” should not be effected by cannabinoids of any variety… australian medical cannabis observatory Cannabinoid Receptors • But cannabinoids still DO have effects in “double knockout mice”! • Cannabinoids still able to affect blood pressure, pain, inflammation, and gastric
motility in the absence of CB1 and CB2 receptors… australian medical cannabis observatory Cannabinoid Receptors • Obviously other receptors out there…
• Hunt was on for them!
australian medical cannabis observatory Endocannabinoid Targets
TRPV1 5-HT3 CBR1 CBR2
GlyR GPR18 AEA AEA AEA, 2-AG AEA, 2-AG (allosteric)
AEA NAGly (allosteric) GPR119 GPR55 G protein Receptors
PPARa PPARy Ligand Gated OEA LPI Receptors OEA, PEA AEA, 2-AG Nuclear Receptors ECS Ligands • ECS has 3 major ligand classes
– Endocannabinoids
– Phytocannabinoids australian medical cannabis – Synthetic Cannabinoids observatory The Endogenous Cannabinoids
• Endocannabinoids = Endogenous cannabinoids, interact with cannabinoid receptors
• Not neurotransmitters in the classical sense- more ‘neuromodulators’ The Endogenous Cannabinoids
• Endocannabinoids = Endogenous cannabinoids, interact with cannabinoid receptors
• Not neurotransmitters in the classical sense- more ‘neuromodulators’
• 2 best known are – Anandamide – 2-arachidonyl glycerol (2-AG) The Endogenous Cannabinoids
Anandaminde (AEA) 2-arachidonoylglycerol The Endogenous Cannabinoids
Anandaminde (AEA) • essential fatty acid neurotransmitter, was first isolated in 1992
• partial agonist of CB1 receptors • affinity and efficacy at
CB2 receptors are low • partial agonist at TRPV1 receptors The Endogenous Cannabinoids
2-arachidonoylglycerol • first described in mammals in 1994. • isolated from canine gut in 1995 by Mechoulam et al • 2-AG is a fully agonist of
both CB1 and CB2 receptors. Main pathways of synthesis and degradation of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG).
Membrane Phosphatidylinositol 4,5- Phosphatidylethanolamine Phospholipids Bisphosphonate (PIP2) (PE) Phospholipase C N-acytransferase Phospholipid Derived Diacylglycerol N-arachidonoyl Phospatidylethanolamine Precursors Diacylglycerollipase Phospholipase D (DAG-lipase)
2-arachidonylglycerol Anandamide Endo- 2-AG cannabinoids Monoacylglycerollipase Fatty acid amide hydrolase (MG-lipase) (FAAH)
Degradation Products Glycerol Ethanolamine The Role of Endocannabinoid Signaling in Motor Control Arachidonic Acid A. El Manira, A. Kyriakatos Physiology Published 10 August 2010 Vol. 25 no. 4, 230-238 DOI: 10.1152/physiol.00007.2010 Endocannabinoid ligands
• Produced on demand at post-synaptic site
• synthesized on demand, no evidence for vesicular storage
• Retrograde action on CB1 receptor, preventing neurotransmitter release
• Particularly important in mitigating glutamate release, reducing excitotoxicity Ethan B. Russo and Andrea G. Hohmann, Role of Cannabinoids in Pain Management Chapter 18 of T.R. Deer et al. (eds.), Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches, 181 DOI 10.1007/978-1-4614-1560-2_18 ECS Modulators 2-AG modulators • Synthesis • formed from membrane phospholipid precursors – activation of phospholipase C – activation of diacylglycerol lipase-α • Degradation – Hydrolyzed by fatty acid amide hydrolase (FAAH) into: • arachidonic acid • ethanolamine. ECS Modulators AEA modulators • Synthesis • 2-AG synthesized from diacylglycerol by diacylglycerol lipase
• Degradation – Hydrolyzed by monoacylglycerol lipase (MAGL) into: • arachidonic acid • glycerol Metabolic role of αβ-hydrolase family (ABHD6, ABHD12) The Components of the Endocannabinoid System
• Just to introduce some complexity… – Atypical receptors – Agonist trafficking – Ligand types – Receptor dimerisation – ‘Promiscuity’
australian medical cannabis observatory Ligand Variations • Orthosteric binding sites – Full agonist – Partial agonist – Antagonist – Inverse antagonist
• Allosteric binding sites – Change HOW ligands bind Ligand Variations
• Orthosteric binding sites – Full agonist (100% activation) • Synthetic cannabinoids at CBR1 – Partial agonist (<100% activation) • THC at CBR1 – Antagonist (competes with binding site) • CBD at CBR1 – Inverse antagonist (turns off signal) • Rimonabant Laura M. Borgelt, Kari L. Franson, Abraham M. Nussbaum and George S. Wang The Pharmacologic and Clinical Effects of Medicinal Cannabis Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy Volume 33, Issue 2, February 2013, Pages: 195–209, Ligand Variations • Allosteric binding sites • Create conformational changes, affect binding – Positive allosteric modulators
– Negative allosteric modulators • pregnenolone australian medical cannabis observatory Cannabinoid Receptors Can Activate Different G Protein Subtypes
• Same receptors…
• Depends on which agonist activates the receptor: “agonist trafficking”
• An assortment of keys opens the same lock, but the door opens into different rooms Biased Signalling Allosteric Interactions
Response 1 Response 2 Response 1 Response 2 Response 1 Response 2 Response 1 Response 2
G protein-coupled receptors in cardiac biology: old and new receptors Cannabinoid Receptor Dimerization
• Turns out, cannabinoid receptors like to play with others
• Only fairly recently discovered
australian medical cannabis observatory Cannabinoid Receptor Dimerization
• At first it was thought that only ‘homodimers’ could occur
• Heterodimerisation now well-described
australian medical cannabis observatory Phenomenally Complicated…
…and more than just a little beautiful. So, what does it all do…? Relax. Eat. Sleep. Forget. Protect. australian medical cannabis Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: endogenouscannabinoid observatory receptor ligands with neuromodulatory action. Trends Neurosci. 1998 Dec;21(12):521-8. Review. Erratum in: Trends Neurosci 1999 Feb;22(2):80. So- what’s it all for?
• General strategy of action is to help cells, tissues and organs re-establish physiological steady state after acute or chronic perturbations of homeostasis
• Ubiquitous, and pleiotropic (Pleiotropy occurs when one gene influences multiple phenotypic traits)
australian medical Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor cannabis ligands with neuromodulatory action. Trends Neurosci. 1998 Dec;21(12):521-8. Review. Erratum in: Trends observatory Neurosci 1999 Feb;22(2):80. Pleio…what now? • ECS major focus for medicine • can target several disorders at the same time (e.g., depression and pain)
australian medical cannabis observatory Homeostasis
changes due to stress/ disease are easily counteracted by compensatory mechanisms
Optimum Function System System activity
australian medical cannabis observatory System activity function function in points =shift set permanent permanent loss gainor of Homeostasis easily counteracted compensatoryby changes changes due disease to stress/ are australian Optimum Optimum Function mechanisms observatory cannabis medical Homeostasis
changes due to stress/ disease are easily counteracted by compensatory mechanisms
Optimum Function System System activity
australian medical cannabis observatory “Ideal” pharmacological approach for multi-factorial disorders
Traditional Approach ‘Ideal’ approach
• Should be a rationalized “multi-target” drug, or a combination • the idea of target selective drugs of drugs, possibly designed using models predictive of both efficacy and safety.
• Should be “pro-homeostatic”, designed to preserve the time and tissue-specificity of homeostasis and possibly cope with • idea of ultra-potent drugs administered no matter when Vs. • its maladaptive adjustments (which occur much more rapidly, e.g., in a developing brain).
• Should be “multi-modal”, in order to deal with the often • Idea of tissue-selective drugs concurring imbalance of more physiological “modes” (cell plasticity, cell cycle, immune response, energy control). Conflict australian medical cannabis observatory In summary…
• We are only beginning to understand the complexity of the endocannabinoid system
australian medical cannabis observatory In summary…
• We are only beginning to understand the complexity of the endocannabinoid system
• …and it’s importance.
australian medical cannabis observatory In summary…
• We are only beginning to understand the complexity of the endocannabinoid system
• …and it’s importance.
• Huge potential to change the well-being of patients
australian medical cannabis observatory A Little Bit of Botany…
The Cannabis Plant
australian medical cannabis observatory So… • What is Cannabis?
– Is it a plant?
– Is it a drug?
australian medical – Is it a medicine? cannabis observatory australian medical cannabis observatory Botanically speaking… Family: Cannabaceae Botanical nomenclature: Cannabis sativa Cannabis indica
Common names: Pot, weed, cannabis, ganja, marijuana, hemp, reefer.
Part used: Medicinally: Dried unfertilised female inflorescence, Resin glands (aka hashish), leaves
Graphic representation of Cannabis sativa (L), showing seeds, stamens, leaves, ovaries and Industry: Seeds (i.e. oil, protein) and inflorescence. Photo from Kohler (1887) fibre (i.e. Textiles, paper, building material) A VERY close relative?
Cannabis Hops Cannabis spp. genomes are 153.8 kbp in length Humulus spp. genomes are 153.7 kbp in length Cannabis Morphology
The short, broad leaf exhibited by Cannabis indica, AKA broad-leaf drug (BLD) variety.
The long, narrow leaf seen in Cannabis sativa, AKA narrow-leaf drug (NLD) variety. australian medical cannabis observatory Nomenclature Debate…
Hillig KW. A chemotaxonomic analysis of terpenoid variation in Cannabis. Biochemical Systematics and Ecology. 2004;32:875-91. BLD – Broad Leaf Drug: NLD – Narrow Leaf Drug: Cannabis indica ssp. afghanica Cannabis indica ssp. indica
BLH – Broad Leaf Hemp: NLH – Narrow Leaf Hemp: Cannabis indica ssp. chinensis Cannabis sativa ssp. sativa
Graphic representation of present day ranges of various Cannabis biotypes. From Clarke & Merlin 2016.
Cannabis Morphology
The seeds of Cannabis, a great nutritional The fibre obtained from Cannabis stalks, used source of oil and protein. throughout human history for millennia. Ideal Cannabis Classification Scheme
• Combines shape, content and purpose • Basic class based on primary cannabinoid (e.g. Type I for THC) • Plant morphology (e.g., broad- leaflet, compact vs. tall, spindly) • Specific cannabinoid content • Specific terpenoid content • Scent • Taste (when vaporized) • Uses/Effects (patient-oriented) australian medical cannabis observatory Quite detailed profiles
australian medical cannabis observatory Sex is Important…
• Female plants are what is desired.. • Where trichomes are located • Source of phytocannabinoids
• Males are (?almost) useless • Produce pollen • Fertilize flowers • Stops trichomes Cannabis Morphology Stamens Pollen
The androecium, or “male place” of the Cannabis plant comprised The female inflorescence made up of many smaller of filaments and anthers, collectively known as stamens. florets and populated with pistils/stigmas upon which pollen fertilises the ovary. Cannabis Morphology Pistils / Stigmas Glandular trichomes
Magnified glandular trichomes on Cannabis plant.
The covering of glandular trichomes on a female Cannabis plant. Hemp trichome types.
(A) Unicellular non-glandular trichome; (B) cystolythic trichomes; (C) capitate sessile trichome; (D) capitate-stalked trichome; (E) simple bulbous trichome; (F) complex bulbous trichome. Cannabis Phytochemistry
Is also complicated… • One of the most studied plants • People just think about ‘Phytocannabinoids’… Cannabis Phytochemistry
Is also complicated… • One of the most studied plants • People just think about ‘Phytocannabinoids’…
It’s so much more than that…! 120 terpenes 13 ketones 50 hydrocarbons 12 aldehydes
34 sugars 11 steroids 20 alkaloids 7 alcohols 19 flavanoids 2 pigments 16 phenols Phytocannabinoids
australian medical cannabis observatory Cannabis Phytochemistry The Phytocannabinoids
Tetrahydrocannabinol (THC)
Cannabidiol (CBD) General Characteristics of the Phytocannabinoids • Produced by the plant as an acid • Lipid soluble • Naturally, fairly low yield • These acids are unstable, and naturally decarboxylate. Faster with heat australian medical cannabis observatory Decarboxylation
CO2
Tetrahydrocannabinolic acid (THCA) Tetrahydrocannabinol (THC)
australian medical cannabis observatory Cannabinoid Phytochemistry
Tetrahydrocannabinol (THC) Structure Cannabidiol (CBD) Structure
Pharmacological actions attributed to THC Pharmacological actions attributed to CBD
Analgesic (Rahn & Hohmann, 2009) Anticonvulsant (Jones et al. 2010)
Antiemetic (Haney et al. 2007; Hollister 1971; Machado et al. 2008) Antagonizes effects of THC- ‘antipsychotic?’ (Pertwee 2008)
Antiinflammatory (Hampson et al. 1998) Analgesic (Davis & Hartoum, 1983)
Antipruritic (Neff et al. 2002) Antiinflammatory (Booz, 2011)
Bronchodilator (Williams et al. 1976) Antiemetic / Antinausea (Rock et al. 2010)
Muscle relaxant (Kavia et al. 2010) Anxiolytic (Russo et al. 2005; Campos & Guimares, 2008)
Antioxidant, Neuroprotective (Hampson et al. 1998) Antioxidant (Hampson et al. 1998)
symptoms of Alzheimer’s (Eubanks et al. 2006) Neuroprotective (Hampson et al. 1998) Cannabichromene (CBC)
• Discovered 1966 • potent anandamide uptake inhibitor • ? modulate the endocannabinoid system Cannabichromene similarly to CBD Weak analgesic (Turner et al. 1980) Antiinflammatory (Davis & Hatoum, 1983)
Antimicrobial (Turner & ElSohly, 1981) Cannabigerol (CBG)
• Discovered 1964 • Pentyl cannabinoid precursor molecule • weak partial agonist of CB and CB 1 2 Cannabigerol Analgesic (Cascio et al. 2010) • anandamide reuptake Antiinflammatory Antifungal (ElSohly et al. 1982) inhibitor Antipsoriatic (Wilkinson & Williamson 2007) Tetrahydrocannabivarin (THCV)
• Bimodal activity
• CB1 antagonist at low doses
• CB1 weak agonist at high doses Tetrahydrocannabivarin THC antagonist (Pertwee et al. 2007) • mild psychoactive Anticonvulsant (Hill et al. 2010) properties Improved glucose tolerance (Wargent et al. 2010) Cannabinol (CBN)
• Discovered 1896 • Still a dark horse.
• partial agonist at CB1 and CB2 • weaker than THC Cannabinol Antipsoriatic (Wilkinson & Williamson 2007)
Sedative (Musty et al. 1976) Antimicrobial against MRSA (Appendino et al. 2008) Terpenes
• Perhaps the commonest occurring natural chemical
• Up to 60% of natural chemicals are terpenes
• Over 50,000 known Terpenes are Legos… isoprene
myrcene limonene menthol
or or OH Terpenes Terpene Phytochemistry
Limonene Enhanced antidepressant Anxiolytic (Carvahlo-Freitas & Costa, 2002) CBD anxiolytic effects Immunostimulant if inhaled (Komori et al. 1995) Antioxidant Enhanced anti-GORD THC Apoptosis of breast cancer (Viguishin et al. 1998) effects
Beta-Myrcene CBD Enhanced anti-inflammatory Antiinflammatory (Lorenzetti et al. 1991) effects Analgesic (Rao et al. 1990) Sedative & hypnotic (do Vale et al. 2002) THC Enhanced THC effects Muscle relaxant (do Vale et al. 2002)
Alpha-pinene CBD Enhanced anti-inflammatory effects Antiinflammatory (Gil et al. 1989) Bronchodilatory (Falk et al. 1980) THC Enhanced bronchodilatory effects
(Cannabis Revealed, Bonnie Goldstein) Phytocannabinoids
• All plants can be manipulated to human purpose (eg grape (Vitis spp))
• Cannabis no exception
• Traditionally exploited to increase amount of psycho-active ∆9-THC
australian medical cannabis observatory Phytocannabinoids
• Currently horticultural techniques are being used to develop “chemovars” (cloned plants), “legitimate” medicinal products
• Treasure hunt is on, for novel ‘landraces’ which could yield undiscovered phytocannabinoids
australian medical cannabis observatory Cannabis Strains Chemotypes / Chemovars
• Cannabis sativa exists in different chemical variants, showing chemical but sometimes also morphological differences, known as chemotypes (Small and Beckstead 1973).
• Three different principal chemotypes were first identified…
australian medical cannabis observatory Cannabis chemotypology (Ernest Small)
Type 1 Type 2 Type 3 ‘Drug Type’ ‘Intermediate Type’ ‘Fibre Type’ Low CBD/THC content ratio Low ratio CBD:THC 10:1 – 1:1 High ratio CBD:THC 27:1 – 10:1 Usually due to high THC-content Combination effects CBD dominant effects THC-rich medicine May or may not be psychoactive Non-psychoactive and non-sedating THC dominant effects (CBD buffers THC effects) allowing for daytime use for many Not only recreational Pain, inflammation, mood, sleep, Pain, inflammation, mood, epilepsy Medical dose can be found nausea Sleep, pain, nausea, mood, appetite australian medical cannabis observatory Small and Beckstead 1973 The Entourage Effect
• first described in 1998 Shimon Ben-Shabat & Raphael Mechoulam
australian medical cannabis observatory The Entourage Effect
• first described in 1998 Shimon Ben-Shabat & Raphael Mechoulam
“Together, all the components of the cannabis plant may exert some therapeutic effect, more than any single compound alone.
While science has not yet shown the exact role or mechanism for all these various compounds, evidence is mounting that these compounds work better together than in isolation: The Entourage Effect
• first described in 1998 Shimon Ben-Shabat & Raphael Mechoulam
“Together, all the components of the cannabis plant may exert some therapeutic effect, more than any single compound alone.
While science has not yet shown the exact role or mechanism for all these various compounds, evidence is mounting that these compounds work better together than in isolation:
That is the entourage effect” The Entourage Effect
• Marinol® (dronabinol, synthetic THC) was approved in the USA in 1985 for treatment of nausea associated with chemotherapy, and for AIDS-wasting in 1992.
• This single component medicine was never well accepted by patients in comparison to whole cannabis.
australian medical cannabis observatory Entourage Effect • Is there a mechanistic benefit? • Maybe… – affect multiple targets within the body – improve active ingredients absorption – minimize adverse side effects.
australian medical Wagner H, Ulrich-Merzenich G. Synergy research: approaching cannabis a new generation of phytopharmaceuticals. Phytomedicine. observatory 2009 Mar;16(2-3):97-110. Bell curve for CBD
Gallily Yekhtin Hanuš Overcoming the Bell ‐Shaped Dose‐Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol Pharmacology & Pharmacy, 2015, 6, 75‐85 Bell curve cannabis- CBD
Pure CBD shows greatest pain Clone 202 threshold at 5 mg before plummeting again australian medical cannabis maximum effect of the 202 extract is greater than the maximum observatory effect of the pure CBD extract Bell curve cannabis- CBD
CBD shows greatest pain threshold Clone 202 extract shows increasing at 5 mg before plummeting again pain threshold up to the maximum amount of extract
maximum effect of the 202 extract is greater than the maximum effect of the pure CBD extract Epidiolex • Supposedly, CBD only…
• Not the case
• A little taste of other cannabinoids… australian medical cannabis observatory Not just Cannabis spp. The Entourage Effect In Summary • Cannabis spp. a rich treasure trove of medicinal compounds • Evidence currently exists for therapeutic approaches using botanical product • Entourage effect intriguing! australian medical cannabis observatory A Little Bit of Pharmacology…
What the body does to cannabinoids- and what cannabinoids do to the body… australian medical cannabis observatory Finding the Right Balance
Desirable effects Undesirable effects Pain, N&V CB1 Stimulation Psychoactive Orexigenesis Decreased insulin resistance Peripheral CB1 Stimulation Increased gastric motility
Decreased inflammation CB2 Stimulation Immunosuppression
Cardiovascular Decreased pain / anxiety Inhibition of EC metabolism
australian medical Pál Pacher and George Kunos Modulating the endocannabinoid system in human health and disease: successes and failures FEBS J. cannabis 2013 May ; 280(9): 1918–1943. doi:10.1111/febs.12260. observatory Pharmacokinetics…
australian medical cannabis observatory Pharmacokinetics • Absorbtion
• Distribution
• Metabolism
australian medical • Excretion cannabis observatory Pharmacokinetics of THC THC Metabolism Serum Protein Binding Administration Hepatic microsomal, Lipoproteins, albumin Non-microsomal, Lungs, Intestine, Colon, Skin extrahepatic
Absorption Metabolites Tissue Storage THC concentration in extracellular water Biliary Excretion Fat, Protein EHC THC concentration at site of action Hair, saliva, sweat Renal Excretion Cannabinoid Receptors Glomerular Filtration Tubular Secretion Other Targets of Action Passive Reabsorbtion THC effects
Brenneisen, R. 2002. Pharmacokinetics. In Cannabis and Cannabinoids. Pharmacology, Toxicology, and Therapeutic Potential, edited by F. Grotenhermen and E. Russo. Binghamton, NY: The Haworth Press, Inc. Cannabis Pharmacokinetics
• Absorbtion – Inhaled (Smoked) • Passive diffusion alveolar capillaries • 10-20% absorbed • Onset = seconds to minutes (similar to IV) • Duration of 2-3 hours • Elimination t1/2= 20 hours • Elimination via urine (20%) and australian medical faeces (65%) cannabis observatory Cannabis Pharmacokinetics • Absorbtion – Inhaled / smoked • 40% of active ingredients lost in side stream +/- combustion • Maximum of 27% of remaining active ingredients can be absorbed
Maximum THC absorbed for 1g of cannabis with 10% of THC = 16.3 mg Cannabis Pharmacokinetics • Smoked bioavailability ranges from 2% - 56%. • variance stems from – parameters between test subjects – parameters of the test subjects themselves • temperature and duration of heating the cannabis • time between each inhalation • number of inhalations • length of inhalation australian medical cannabis • patient’s lung capacity observatory Cannabis Pharmacokinetics • Absorbtion – Inhalation- practical considerations… • Rapid delivery- rapid onset • Easily titratable
australian medical cannabis observatory Cannabis Pharmacokinetics • Absorbtion
– Inhalation- Smoking vs. Vapourisation
australian medical cannabis observatory Cannabis Pharmacokinetics
Smoking
Plant material starts to combust at 200°C
88% Non-Cannabinoids
Smoke associated with respiratory disease Cannabis Pharmacokinetics
Smoking Vapourisation
Oils start to Plant material starts vapourise at 140°C to combust at 200°C (Optimum at 170°C)
88% Non-Cannabinoids 95% Cannabinoids
Smoke associated with No Smoke respiratory disease Eisenberg E, Ogintz M, Almog S. The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study. J Pain Palliat Care Pharmacother. 2014 Sep;28(3):216-25. Cannabis Pharmacokinetics
• Absorbtion – Oral – rate of absorption and bioavailability of THC in oral administration is much lower than inhalation – ranges between 2% - 20%, with a higher variance between patients. – bioavailability in oral administration is around 1/3 of that during inhalation. Grotenhermen 2003 – A significant portion of this variance is a result of extensive metabolism performed in australian the liver. medical cannabis – 3 metabolites to consider: observatory • THC, THC-COOH and 11-OH-THC. Oral
• Effects appear approximately 90 minutes after ingestion, reach their maximum after 2-3 hours and last for about 4-12 hours
• About 50% of orally administered THC is metabolized to 11-hydroxy-THC by hepatocytes before entering the systemic bloodstream.
• Pharmacodynamic studies of the metabolite are sparse – Maybe 4-fold > psychoactivity than THC (animal studies)
australian medical cannabis observatory Issues with edibles
• In March 2014, the Colorado Department of Public Health and Environment reported a death linked to cannabis overconsumption without evidence of poly-substance use. • the individual consumed a cookie with 10 mg of THC. • After 30 minutes, after no effects consumed an additional 50 mg of THC within 30 to 60 minutes. • The individual became combative and jumped off a fourth floor balcony australian medical cannabis (Doesn’t seem to happen in The Netherlands) observatory Cannabis Pharmacokinetics • Distribution
• THC initially penetrates high vascularity tissues and organs with such as the liver, jejunum, spleen, heart, lung, kidney, mammary gland, placenta, adrenal cortex, muscle, thyroid and pituitary gland, and this results in a rapid decrease of the plasma concentration of THC • THC distribution volume (V) is around 3.4L/kg. • THC concentration in brain double that of blood after 30 minutes – higher levels in the cerebellum and the occipital and frontal cortex – lowest levels were observed in the medulla oblongata. • significant accumulation occurs in tissues with less vascularity and eventually in fat • Fat is the major long-term storage site • unknown if the THC is stored in fat as unaltered THC or as a THC hydroxy metabolite Ashton, C. Heather, 2001 Cannabis Pharmacokinetics • Metabolism – the three main phytocannabinoids. • THC • cannabidiol (CBD) • cannabinol (CBN) – metabolised by cytochrome P450 enzymes THC Metabolism in the Liver and First-Pass Effect
• After THC absorbed into the bloodstream, distributed to the liver
• undergoes metabolism by the cytochrome CYP-450
• The main metabolite of THC is 11-OH-THC
• undergoes secondary metabolism to THC-COOH THC Metabolism in the Liver and First-Pass Effect
• Through GIT, THC first arrives at the liver directly (before being absorbed in the systemic bloodstream), where primary metabolism takes place, also known as ‘the first-pass effect’
• results in a lower rate of absorption and lower THC plasma levels after oral administration relative to those observed after the other routes of administration.
• primary metabolite 11-OH-THC has a physiological activity range similar, but not necessarily identical, to that of THC. • higher potency and crosses the blood-brain barrier more easily,
• secondary metabolite THC-COOH is not attributed any psychoactive activity, probably plays a role in the analgesic and anti-inflammatory effects of cannabinoids.
How interactions could work…
By inhibiting processes that By augmenting processes that Pharmaco- remove those drugs remove those drugs kinetically Cannabinoids Cannabinoids can increase the can decrease activity or effect the activity or of other drugs effect of other drugs Pharmaco- By having the same By having the opposite dynamically “final action” “final action” as those drugs as those drugs How interactions could work…
By inhibiting processes that By augmenting processes that Pharmaco- remove those Cannabis remove those Cannabis kinetically Other drugs can Other drugs can increase the decrease the activity or effect activity or effect of Cannabinoids of Cannabinoids
Pharmaco- By having the same By having the opposite dynamically “final action” “final action” as those Cannabis as Cannabis Pharmacodynamic properties of THC
•Accelerated heart rate (19bmp above average) •Increased feeling of high •Decreased alertness •Increased motor instability
Heart rate (bpm) VAS feeling high (U) VAS alertness (mm)
Zuurman L, Ippel AE, Moin E, van Gerven JM. Biomarkers for the effects of cannabis and THC in healthy volunteers. Br J Clin Pharmacol. 2009 Jan;67(1):5-21. Pharmacodynamic properties of THC Central nervous system
• Low doses of THC, • calming effect is achieved • reduced concentration, • reduced motivation / active participation.
• high doses of THC • more stimulating.
• Best Biomarkers: • Subjective responses • increased heart rate, (peripheral effects of cannabinoid activity) Pharmacodynamic properties of THC • Main Side Effects and Interactions
• physiological phenomena • dizziness, cardiac arrhythmia (tachycardia or bradycardia), low blood pressure and blood sugar levels, increased appetite, red eye, headaches, abdominal pain, fatigue, impaired coordination, loss of balance and dryness of mucous membranes such as the mouth and eyes
• cognitive effects, • short-term memory loss, impaired thinking and changes in space- time perception. Pharmacodynamic properties of THC
In excess
Fainting, big changes in blood pressure, heart rate, blood sugar or respiratory rate.
A high dose of this substance may, in certain cases and for people with a predisposition, cause a temporary outbreak of psychotic episodes, anxiety or hallucinations. A Little Bit of Medicine…
What it’s being used for?
australian medical cannabis observatory What is Cannabis Actually Used For? • Conditions in Clinical Practice Rank order - Hergenrather 2015 – Pain (acute pain, chronic, inflammatory, neuropathic) – Mental disorders(all kinds) – Cancers – Gastrointestinal disorders – Insomnia – Migraine / headaches – Harm reduction, alternative to opioids… – Spasticity – Autoimmune disorders – Neurodegenerative disorders – Glaucoma – Skin diseases australian – Epilepsy, Autism, Tourettes, ADD, Dystonia, Dementia • medical – AIDS and other infections cannabis observatory What do we know for sure…?
• >85% support for medicinal cannabis in community
australian medical cannabis observatory What do we know for sure…?
• >85% support for medicinal cannabis in community
• Maybe 100,000 (0.5%) Australians are already using illicit cannabis for medicinal purpose
australian medical cannabis observatory What do we know for sure…?
• >85% support for medicinal cannabis in community
• Maybe 100,000 (0.5%) Australians are already using illicit cannabis for medicinal purpose (25,000? NZ)
• CONSIDERABLY easier to source ‘illicit’ medicinal cannabis than ‘prescribed’ medicinal cannabis australian medical cannabis observatory What do we know for sure…?
• Just ENORMOUS overseas experience…
>200,000 officially approved patients >30,000 officially approved patients Family practitioners considered as ‘proper doctors’ Only time for 3 conditions, today…
• Pain
• Seizures
• Cancer australian medical cannabis observatory Pain Pain is THE issue for Users of Medicinal Cannabis.. 1000 900 800 700 600 500 400 300 200 100 0 Pain is THE issue for Users of Medicinal Cannabis.. 1000 900 800 700 600 500 400 300 200 100 0 Patients are turning to Cannabis-based medication
Corroon, J.M., LK; Sexton,M, Cannabis as a Substitute for Prescription Drugs- a Cross Sectional Study. Journal of Pain Research, 2017. 10: p. 989-998. ECS & Pain
Ow. Pain Pathways
australian medical cannabis Role of Cannabinoids in Pain Management Ethan B. Russo and Andrea G. Hohmann in observatory T.R. Deer et al. (eds.), Comprehensive Treatment of Chronic Pain by Medical, Interventional, and Integrative Approaches, 181 DOI 10.1007/978-1-4614-1560-2_18, © American Academy of Pain Medicine 2013 “So where’s the evidence?” “So where’s the evidence?” • Trials have been terribly difficult (legality)
australian medical cannabis observatory “So where’s the evidence?” • Trials have been terribly difficult (legality) • Material very variable
australian medical cannabis observatory What people are using for relief…
What people have used for trials. australian medical cannabis observatory Veraga, D.e.a., Compromised External Validity: Federaly Produced Cannabis Does Not Reflect Legal Markets. Nature Scientific Reports, 2017. 7: p. 1-8. Trials with smoked cannabis
• Abrams DI, Jay CA, Shade SB, et al. Cannabis in painful HIV- associated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515–21.
• Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo- controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9(6):506–21.
• Wallace M, Schulteis G, Atkinson JH, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology. 2007;107(5):785– 96.
• Ellis RJ, Toperoff W, Vaida F, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672–80.
• Ware MA, Wang T, Shapiro S, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182(14):E694–701. australian medical cannabis observatory Bunch of Nobodies…
• MARIE C. McCORMICK (Chair), Sumner and Esther Feldberg Professor, Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA • DONALD I. ABRAMS, Professor of Clinical Medicine, University of California, San Francisco, and Chief of Hematology–Oncology Division, Zuckerberg San Francisco General Hospital, San Francisco • MARGARITA ALEGRÍA, Professor, Departments of Medicine and Psychiatry, Harvard Medical School, and Chief, Disparities Research Unit, Massachusetts General Hospital, Boston • WILLIAM CHECKLEY, Associate Professor of Medicine, International Health, and Biostatistics, Division of Pulmonary and Critical Care, Johns Hopkins University, Baltimore, MD • R. LORRAINE COLLINS, Associate Dean for Research, School of Public Health and Health Professions and Professor, Department of Community Health and Health Behavior, State University of New York at Buffalo–South Campus • ZIVA D. COOPER, Associate Professor of Clinical Neurobiology, Department of Psychiatry, Columbia University Medical Center, New York • ADRE J. dU PLESSIS, Director, Fetal Medicine Institute; Division Chief of Fetal and Transitional Medicine; and Director, Fetal Brain Program, Children’s National Health System, Washington, DC • SARAH FELDSTEIN EWING, Professor, Department of Child and Adolescent Psychiatry, Oregon Health & Science University, Portland • SEAN HENNESSY, Professor of Epidemiology and Professor of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia • KENT HUTCHISON, Professor, Department of Psychology and Neuroscience and Director of Clinical Training, University of Colorado Boulder • NORBERT E. KAMINSKI, Professor, Pharmacology and Toxicology, and Director, Institute for Integrative Toxicology, Michigan State University, East Lansing • SACHIN PATEL, Associate Professor of Psychiatry and Behavioral Sciences, and of Molecular Physiology and Biophysics, and Director of the Division of Addiction Psychiatry, Vanderbilt University Medical Center, Nashville, TN • DANIELE PIOMELLI, Professor, Anatomy and Neurobiology, School of Medicine and Louise Turner Arnold Chair in Neurosciences, Department of Anatomy and Neurobiology, University of California, Irvine • STEPHEN SIDNEY, Director of Research Clinics, Division of Research, Kaiser Permanente Northern California, Oakland • ROBERT B. WALLACE, Irene Ensminger Stecher Professor of Epidemiology and Internal Medicine, Department of Epidemiology, University of Iowa Colleges of Public Health and Medicine, Iowa City • JOHN WILEY WILLIAMS, Professor of Medicine, Duke University Medical Center, Durham, NC australian medical cannabis observatory australian medical cannabis observatory “So where’s the evidence?” • Trials have been terribly difficult (legality) • Material very variable • Emerging surrogate evidence
australian medical cannabis observatory “So where’s the evidence?” • Trials have been terribly difficult (legality) • Material very variable • Emerging surrogate evidence – Demographic data – Prescribing data australian medical cannabis observatory Where’s the evidence? • Epidemiology
australian medical cannabis observatory Public Health Implications
States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate without medical cannabis laws.
(95% CI, −37.5% to −9.5%; P = .003) compared with states
Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999–2010. JAMA internal medicine. 2014;174(10):1668-1673. australian medical cannabis observatory Where’s the evidence? • Why? – patients choosing to initiate medical cannabis over opioid analgesics
– patients already on opioid analgesics finding decreased requirements when using medical cannabis
– medical cannabis laws lead to decreases in polypharmacy— particularly with benzodiazepines—in people taking opioid analgesics, overdose risk would be decreased Public Health Implications
Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical Cannabis Laws and Opioid Analgesic Overdose Mortality in the United States, 1999–2010. J AMA internal medicine. 2014;174(10):1668-1673. australian medical cannabis observatory Where’s the evidence? • Prescribing Practice
australian medical cannabis Bradford AC, Bradford WD. Medical Marijuana Laws Reduce Prescription Medication Use In Medicare observatory Part D. Health Aff (Millwood). 2016 Jul 1;35(7):1230-6. Where’s the evidence? • Total estimated Medicaid savings $260.8 million in 2007, to $475.8 million in 2014
• If all states had legalized medical marijuana in 2014, “The national savings for fee-for-service Medicaid would have been approximately $1.01 billion” • • This works out to an average per state savings of $19.825 million a year
Bradford AC, Bradford WD. Medical Marijuana Laws May Be Associated With A Decline In The Number Of Prescriptions For Medicaid Enrollees. Health Aff (Millwood). 2017 May 1;36(5):945-951.
Acute Pain? • Probably not that useful…
• But acute exacerbations of chronic pain? – Definitely.
australian medical cannabis observatory Can Medicinal Cannabis Meet 2 Criteria? • Make your patient feel better?
• Benefits exceed the risks (by a wide margin)?
australian medical cannabis observatory Seizure Disorder
australian medical cannabis observatory Very early…
• A treatise, written in the 15th century by Ibn al-Badri, preserved as a manuscript in Paris, tells that the poet Ali ben Makki gave hashish to Zahir-ad-din Muhammed, the epileptic son of the Chamberlain of the Caliphate Council in Baghdad.
• Zahir had no more seizures, but had to stay on the drug ever after.
australian medical Rosenthal, F. (1971) The Herb- Hashish cannabis versus Medieval Society, EJ Brill, Leiden, NL observatory What’s doing the work…? • Looks like CBD
• THC less likely
• Other strong contenders… australian medical cannabis observatory CBD: Anti-seizure & Anti-epileptic effects • CBD has anticonvulsant effects in > 6 seizure models in rats and mice; independently of CNS CB1 receptors (Jones et al, Seizure 2012; Hill et al, Endocannabinoids 2013:164-204; Hill et al, Brit J of Pharm 2013; Karler & Turkanis, J Clin Pharm 2013) • CBD reduces epileptiform activity in vitro (Jones et al. 2010, J Pharm Exp Ther) • CBD reduces mortality in pentylenetetrazol (PTZ) induced seizures (Jones et al. 2010, J Pharm Exp Ther) Excitatory Glutamergic Synapse
http://www.nature.com/nm/journal/v14/n9/extref/nm.f.1869-S1.swf Anticonvulsant Mechanisms of CBD
Stabilizes ion channels (lamotrigine phenytoin levetiracetam )
Enhances GABA receptor (Valproate, carbamazepine)
Blocks NMDA receptor (Felbamate) Nature Reviews Neurology 8(12) · November 2012 Multiple Neuroprotective Pathways…?
Excitotoxicity (cell damage due to excessive excitation and calcium signaling)
Reactive oxygen species (ROS) and nitrosylation - cannabinoids as antioxidants Innate Immune Microglial activation Response
Pro-inflammatory cytokines Neuroinflammation
Vasodilation and cerebral perfusion
Neurogenesis – growth of new neurons from neuronal stem cells
From Gerdeman, UIC, 2017 “Pleiotropic Neuroprotection” What about THC as anticonvulsant…?
• Conflicting results in animals – both anticonvulsant and proconvulsant – Anticonvulsant through inhibition of glutaminergic excitatory transmission – Proconvulsant through inhibition of release of GABA – Tolerance develops limiting clinical use for epilepsy – Concerns of psychoactivity and effects on developing brain • Clinically, low doses can be helpful when weaning off AEDS • THC 10 mg per 1 ml preparation allows for low doses to be added to • CBD regimen (0.1 ml = 1 mg) • Some patients have better results with low dose THC added to CBD regimen with no concern of psychoactivity What about other phytocannabinoids?
• CBDV (cannabidivarin) – Anticonvulsant in multiple animal models – Acts independently of CB1 receptor/may act at CB2 – Inhibits uptake of anandamide – Activates TRPV1/1 and TRPA1 channels – Oral efficacy retained – Additive effects when co-administered with CBD • THCA – potent anti-inflammatory/anecdotal anticonvulsant • CBN (cannabinol) – conflicting results • Delta-8-THC – early tolerance australian • Delta-9-THCV – effective in vivo and in vitro medical cannabis Santos, et al. "Phytocannabinoids and epilepsy." observatory Journal of clinical pharmacy and therapeutics (2015) Who’s the expert?
Dr Bonnie Goldstein
australian medical cannabis observatory Current Series
• Diagnosis of treatment resistant epilepsy • At least three months on tested whole plant oil extract • 201 patients aged 5 months – 18 years of age • Average number of prior AEDs: 12 (range 2 – 22) • Average number of concomitant AEDs at onset of treatment: 3 (range 0 – 7); 15 patients not taking AEDs at onset of CBD treatment (7%) • Common comorbidities: global delay, CP, Autism, CVI, feeding difficulties, growth delay, precocious puberty, behavioral issues • Strains and CBD:THC ratios of oils used: – Charlotte’s Web: 27:1 australian medical – ACDC: 28:1, 25:1, 24:1, 15:1 cannabis observatory Current series of n=201
80 70 60 50 40 30 20 10 0 Worsening No Response Reduced 25-49% 50-74% 75-99% Seizures Severity Reduction Reduction Reduction /Duration Current series of n=201
• 68% of patients had >50% reduction of seizures • 27 seizure-free patients- 8 now AED free • 40% weaned >1 AED • Negative side effects: drowsiness, diarrhea • Positive side effects: more alert, better mood, better sleep, more energy, • better response to therapy, improved appetite, improved focus, “able to argue”, no ER visits or hospitalizations, less need for rescue medication, two patients with Type 1 DM reported more stable glucose Dosing Regime for Whole Plant Oil Extract • 1 mg/kg/day every 8 hours starting dose, increase in increments of 0.5 – 1 mg/kg/day every 2 weeks (oral, sublingual, G-tube) – Average dose ~ 5 – 12 mg/kg/day • Can change strains and/or CBD:THC ratios if not responding – No tolerance to CBD – CBD “saturation” – Check AED levels – THCA oil – Cost is an issue for most patients australian medical cannabis observatory Paediatric Considerations
• Concentrated – For example, 50 mg/ml, 100 mg/ml, 200 mg/ml • Consistent in strain – Different strains (even if high CBD) can wreak havoc in pediatric patients • Laboratory Tested – Potency, pesticides, mold/microbes, residual solvent (if used) • Affordable (i.e. 5 cents/mg vs 35 cents/mg) • Reliable supply – Patients who start treatment may wean other medications Catastrophic if oil not available Pearls
• Start low-dose high ratio CBD:THC ratio for majority of patients, titrate up for desired effects • CBD dosing: higher for cancer and epilepsy, lower for most other conditions • THC dosing: 0.5 mg – 1 mg added to already existing CBD regimen (minimizes psychoactivity) – titrating up for desired effect • Consider changing strain or ratio Is there a link between the ECS and epilepsy? • The endocannabinoid system is activated by seizures.
• increasing CB1 receptor activity has anti-seizure effects (1). • In mice given systemic kainic acid to induce seizures, hippocampal anandamide levels rise after seizures.
• When neurons cultured from the hippocampus are exposed to CB1 receptor antagonists, prolonged seizure discharges are produced
these discharges are suppressed by CB1 receptor agonists • Drugs that reduce the metabolism of endocannabinoids and thereby increase their activity, help to control experimentally induced seizures Is there a link between the ECS and epilepsy? • There are defects in the endocannabinoid system in persons with epilepsy. • In one study, 12 patients with newly diagnosed temporal lobe epilepsy had lower levels (p < .01) of anandamide in spinal fluid as compared to controls • In tissue removed from 30 patients undergoing epilepsy surgery, the levels
of CB1 receptor messenger RNA were lower in some excitatory nerve endings as compared to the specimens obtained post mortem from persons without epilepsy. • reduced expression of diacylglycerol lipase α (DAGL-α), the enzyme that synthesizes 2-AG in postsynaptic neurons (6). (Recall that 2-AG is a fully
efficacious agonist of both CB1 and CB2 receptors.) australian medical cannabis observatory
NEJM Study
• GW Pharmaceuticals phase 3 CDB trial • Randomised Double-blind peer-reviewed study, • 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either: – cannabidiol oral solution (20 mg/kg/day) vs. – placebo – in addition to standard antiepileptic treatment. australian medical cannabis observatory NEJM Study • 14-week trial • median “frequency of convulsive seizures per month decreased” for those in the cannabidiol group 12.4 to 5.9; • Vs. placebo group (14.9 to 14.1) australian medical cannabis observatory NEJM Study
• The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol vs 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08).
• The patient’s overall condition improved by at least one category on the seven- category Caregiver Global Impression of Change Scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02).
• The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures.
• The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo.”
NEJM Study (2)
• GW Pharmaceuticals • Randomised Double-blind peer-reviewed study • 30 Centers • 225 patients with Lennox-Gastaut syndrome and drug- resistant seizures to receive either: – cannabidiol oral solution (20 mg/kg/day) vs. – cannabidiol oral solution (20 mg/kg/day) vs. – placebo australian medical – in addition to standard antiepileptic treatment. cannabis observatory NEJM Study (2)
• median reduction from baseline in drop-seizure frequency during the treatment period:
– 41.9% in the 20-mg cannabidiol group (p=0.005 vs. placebo)
– 37.2% in the 10-mg cannabidiol group (p=0.002 vs. placebo)
– 17.2% in the placebo group australian medical cannabis observatory NEJM Study (2)
• commonest adverse events: – somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. • 6 patients in the 20-mg cannabidiol group & 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. • 14 patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. In summary… • Quite a lot of work already done in this space
• First NEJM Study is a major breakthrough
australian • More to come medical cannabis observatory Cancer
australian medical cannabis observatory Probably the least threatening for physician
• Patients often dying
• Symptomatic control the focus
• Long term issues less of a concern…
australian medical cannabis observatory Frequently suggested… • Cannabis causes cancer? • Nope.
australian medical cannabis observatory Possible, but unproven… • Treatments for Cancer Pathways activated through cannabinoid receptors Strongest indications…
• relieving nausea and vomiting in patients undergoing chemotherapy
• adjunctive analgesic in patients with moderate to severe pain
• appetite stimulant for cancer patients experiencing weight loss and muscle wasting.
• address some of the psychological issues of palliative care australian medical cannabis observatory The Perfect Storm Anorexia Opioid analgesics Chemotherapy Nausea Fatigue Pain Anxiety, depression Every element can be addressed by cannabinoids Cannabinoids in Nausea & Vomiting
• directly block emesis via agonism of CB1 receptors – in the area postrema, nucleus solitarius tract, dorsal motor nucleus in brainstem • indirectly through a retrograde pathway to inhibit other CNS neurotransmitters (serotonin, dopamine) • may also have an effect at the enterochromaffin cells in the GI tract • In > 30 studies, THC and nabilone have been shown to have a similar anti-emetic efficacy as the phenothiazines A Little Bit of Pragmatism…
How does one actually practically use medicinal cannabinoids? australian medical cannabis observatory IS THERE AN APPROPRIATE FURTHER EVALUATION / NO INDICATION FOR REFERRAL MEDICINAL CANNABIS?
YES
ATTEMPT HAVE THEY SOUGHT YES GOOD RESPONSE TO STANDARD TREATMENT NO STANDARD TREATMENT? STANDARD TREATMENT?
NO YES
ARE THEY WILLING TO CONTINUE STANDARD NO CONSIDER TREATMENT MEDICINAL CANNABIS?
YES
START THERAPY: ARE THERE ANY NO EDUCATE ETC. CONTRAINDICATIONS?
YES
LIAISE WITH MONITOR OUTCOMES SPECIALISTS SIDE EFFECTS
FAVOURABLE UNFAVOURABLE RISK / BENEFIT RATIO RISK / BENEFIT RATIO PROCEED NOT A CANDIDATE Preparations
• Cannabis preparations – Cannabis flowering tops, keif, and hashish
– Oils: solvent or supercritical CO2 extracted – Tinctures: cannabis oils diluted with EtOH, glycerin, various oils, and water – Infusing cannabis oils into: olive oil, ghee, other – Salves: cannabis oils blended with other oils – Suppositories: cannabis oil blended with theobroma cacao (cocoa butter) or other oils – Foods, beverages, candies, capsules, etc. australian medical cannabis observatory Types of medicinal cannabis products
• Flos/bud—Good Manufacturing Practice (GMP) certified cannabis buds or flower heads of known delta-9-tetrahydrocannabinol (THC) /Cannabidiol (CBD) percentage
• Oils—varying combinations of THC and CBD
• Liquid capsules—varying combinations of THC and CBD
• Oro-mucosal spray—THC and CBD combination australian medical cannabis observatory Routes of Cannabinoid Delivery
• Pulmonary • Oral • Buccal • Intranasal • Transdermal • Rectal
australian medical cannabis Each have their own pros and cons observatory Things to Consider The Right Patient The Right Condition The Right Dose The Right Route
The Right Timing australian medical cannabis The Right Ratios observatory How to start, for a known patient, with an appropriate condition…
Select ratios
australian medical cannabis observatory How to start…
Select ratios
Select properties australian medical cannabis observatory How to start…
Select ratios
Select properties
Select route australian medical cannabis observatory How to start…
Select ratios
Select properties
Select route
Select dose australian medical cannabis observatory Optimize clinical effects of cannabinoid augmentation by controlling several variables • Method of administration • Dosage • Frequency of use • Cannabinoid ratios, THC:CBD • Carboxylated / decarboxylated ratio, THCA:THC Getting Dosing Right This is a topic of great debate…
australian medical cannabis observatory “But you never know what’s in cannabis…”
Getting Dosing Right You can understand why… • Plant variations – Plant itself – Time of harvest • Patient variations – Individual susceptibility australian medical cannabis – Heavy vs. light users observatory Getting Dosing Right Solution simpler than portrayed…
• Individualized dosing
• Self-titrating australian medical cannabis observatory Getting Dosing Right Entirely justifiable approach…
• Variability of product
• Low toxicity / high dosing limits of product
australian medical cannabis • Not without precedent… observatory Gabapentin Dosing
australian medical cannabis observatory There is already a dose-specific, prescribable cannabinoid… • Dronabinol
• Prescribing guidelines have been used by investigators to derive guidelines for herbal cannabis australian medical Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal cannabis: rational guidelines for dosing. IDrugs. 2004 cannabis May;7(5):464-70 observatory Aggarwal SK, Kyashna-Tocha M, Carter GT. Dosing Medical Marijuana: Rational Guidelines on Trial in Washington State. Medscape General Medicine. 2007;9(3):52. Dosing Equivalents
% THC in plant material Amount of plant material (g) required to obtain:
2.5mg of THC 10mg of THC 30mg of THC 60mg of THC
5% 0.60 1.24 3.70 7.40 10% 0.30 0.62 1.85 3.70 15% 0.16 0.41 1.23 2.46 20% 0.10 0.31 0.93 1.86 25% 0.08 0.25 0.75 1.50 30% 0.05 0.20 0.62 1.24
Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal cannabis: rational guidelines for dosing. IDrugs. 2004 May;7(5):464-70 Dosing Equivalents
Daily amount Daily cannabis amount (grams) Monthly cannabis amount (grams) of THC based Based on equivalent amounts of THC Based on equivalent amounts of THC on Dronabinol dosing model (mg)
T15/C3 T20/C4 T10/C2 T15/C3 T20/C4 T10/C2 Cannabis (15% Cannabis (20% Cannabis Cannabis Cannabis Cannabis (10% THC) THC) (10% THC) (15% THC) (20% THC) THC)
2.5 0.30 0.16 0.10 9.1 4.9 3.0 10 0.62 0.41 0.31 18.9 12.5 9.5 30 1.85 1.23 0.93 56.3 37.4 28.3 60 3.70 2.46 1.86 112.5 74.9 56.6 Rough Calculations are Easy
Weight X [THC]% X bioavailability e.g. for 1g cannabis cigarette of 15% THC 1g X 15% X 25% for smoked =37.5mg THC, if whole joint smoked (could be a lot less, depending on technique) Rough Calculations are Easy
Weight X [THC]% X bioavailability e.g. for 1g cannabis vapourised of 15% THC 1g X 15% X (60-90%- 25% exhaled ≈ 50%) =75mg THC, if whole joint smoked (much better delivery, for same quantity) Rough Calculations are Easy
Weight X [THC]% X bioavailability This is important It’s already available… STRAIN Bedrocan® Bedrobinol® Bediol® Bedica® Bedrolite®
Introduced 2003 2005 2007 2011 2014
Cannabis sativa Cannabis sativa Cannabis Cannabis Cannabis Strain L. ‘Afina’. L. ‘Ludina’. sativa L. sativa sativa ‘Elida’. L. ‘Talea’. L. ‘Rensina
THC (%) 22 13.5 6.3 14 9%
CBD (%) <1 <1 8 <1 <1 Israeli Cannabis Bud or ‘flos’
Type Item THC CBD T0/C24 CBD Medical Cannabis 0% 24% CBD Rich (0.0% - 0.5%) (20% - 28%) T1/C20 CBD Medical Cannabis 1% 20% (0.0% - 2.5%) (16% - 24%) T3/C15 CBD Medical Cannabis 3% 15% (0.5% - 5.5%) (11% - 19%) T5/C10 CBD Medical Cannabis 5% 10% (2.5% - 7.5%) (6% - 14%) T10/C10 Medical Cannabis 10% 10% (6% - 14%) (6% - 14%) T10/C2 Sativa Medical Cannabis 10% 2% THC Rich (6% - 14%) (0.2% - 3.8%) T10/C2 Indica Medical Cannabis 10% 2% (6% - 14%) (0.2% - 3.8%) T15/C3 Sativa Medical Cannabis 15% 3% (11% - 19%) (0.5% - 5.5%) T15/C3 Indica Medical Cannabis 15% 3% (11% - 19%) (0.5% - 5.5%) T20/C4 Sativa Medical Cannabis 20% 4% (16% - 24%) (1% - 7%) T20/C4 Indica Medical Cannabis 20% 4% (16% - 24%) (1% - 7%) Israeli Cannabis Oil
Type Item THC CBD T0/C24 CBD Medical Cannabis 0% 24% CBD Rich Oil (0.0% - 0.5%) (20% - 28%) T1/C20 CBD Medical Cannabis 1% 20% Oil (0.0% - 2.5%) (16% - 24%) T3/C15 CBD Medical Cannabis 3% 15% Oil (0.5% - 5.5%) (11% - 19%) T5/C10 CBD Medical Cannabis 5% 10% Oil (2.5% - 7.5%) (6% - 14%) T10/C10 Medical Cannabis Oil 10% 10% (6% - 14%) (6% - 14%) T10/C2 Medical Cannabis Oil 10% 2% THC Rich (6% - 14%) (0.2% - 3.8%) T15/C3 Medical Cannabis Oil 15% 3% (11% - 19%) (0.5% - 5.5%) T20/C4 Medical Cannabis Oil 20% 4% (16% - 24%) (1% - 7%) Indications for THC-rich Cannabis
Recommended Recommended Gradual E.P. Indication Product for Start Course for Further of Treatment Treatment
Chemotherapy, up to 6 months, nausea, vomiting or T10/C2 T10/C10 → T15/C3 →T20/C4 treatment-associated pain
Stage IV cancer pain T10/C2 T10/C10→T15/C3→T20/C4
THC-rich products for Neuropathic pain of a clear organic source T10/C10 immediate relief + CBD-rich products for long- term treatment AIDS, to improve appetite, relieve vomiting, digestive system symptoms after all accepted medication treatment has been T10/C10 T10/C2→T15/C3→T20/C4 exhausted, who also suffer from severe weight loss (cachexia – more than 10% loss of body weight Indications for THC-rich Cannabis
Recommended Recommended Gradual Indication Product for Start E.P. Course for Further of Treatment Treatment T10/C2→T15/C3→T20/C4 MS– spasticity not responded to conventional treatment T10/C10 If necessary, together with CBD-rich products to alleviate spasmodic states.
PD– unresponsive to conventional treatment options T10/C2 T10/C10→T15/C3→T20/C4 chronic pain or pain from stiffness
Tourette’s Syndrome - Adult patients suffering from a T10/C2 T10/C10→T15/C3→T20/C4 significant disruption of daily life, who have not responded to conventional treatment options
Terminally ill patients (<6m life expectancy) T10/C10 T10/C2→T15/C3→T20/C4 Indications for CBD-rich Cannabis
Recommended Recommended Gradual E.P. Course for Further Indication Product for Start of Treatment Treatment
To T0/C24 Adult epilepsy patients T1/C20 If necessary, combine or concentrate treatment on THC products with slightly higher concentrations, such as: T3/C15 or T5/C10
T1/C20 product Minors suffering from severe uncontrolled epilepsy T0/C24 If necessary, combine treatment with THC product with slightly higher concentrations, such as: T3/C15
To T5/C10To T3/C15To T1/C20To T0/C24 Adults diagnosed with PTSD T10/C10 or If necessary, combine with THC-rich products for T10/C2 immediate relief of symptoms, T15/C3 at most. Indications for CBD-rich Cannabis
Recommended Recommended Gradual E.P. Course for Further Indication Product for Start of Treatment Treatment
Patients with HCC – It is recommended not to use THC T0/C24 T1/C24 if necessary products
Patients suffering from active and proven IBD (Crohn’s disease T5/C10 To T3/C15To T1/C20To T0/C24 or ulcerative colitis)
THC-rich products for immediate relief together with Patients suffering from neuropathic pain of a clear organic T10/C10 CBD-rich products for long-term treatment source Getting Dosing Right The Right Route
australian medical cannabis observatory Patient’s needs determine route of administration
• Rapid titration of acute symptoms? • Inhalation preferred route of administration – quick absorption, high peak concentration and shorter exposure to active ingredients in the bloodstream.
• Chronic and persistent symptoms? • sublingual administration preferred route of administration – relatively slow absorption, low peak concentration and a longer exposure to active ingredients in the bloodstream.
• Is the patient a habitual smoker? • Persons not used to smoking will find it difficult to inhale cannabis using cigarettes. – If inhalation is required, an inhalation device is recommended. australian medical cannabis observatory Patient’s needs determine route of administration
• Does the patient suffer from a medical condition that makes it difficult for them to inhale it as a medicine (eg SOB)? – In these cases, sublingual administration is recommended.
• Age of the patient? – Sublingual/oral administration is recommended for elderly patients and children. – Extraction technique…
• Is the patient taking a THC-rich product? – Inhalation of these products can cause a feeling of intoxication and even anxiety. – In these cases, sublingual administration of oil extracts is recommended. – Advice re: driving, machinery Determining the initial amount of cannabis product
• Need to consider: – THC and CBD are not the only clinically and pharmacologically active cannabinoids in the cannabis plant, there are other components with psychoactive effects. – The effects of THC and CBD are clearly mediated through other cannabinoids, which also have a unique set of effects of their own. – Patient tolerance. – The different routes of administration can affect absorption and bioavailability. – Cannabinoid degradation products, which also have clinical and pharmacological activity and some even have psychoactive effects. australian medical cannabis observatory Israeli Guideline
The recommended initial amount of cannabis for treatment is around 0.6g per day
Therefore:
• The recommended monthly amount of cannabis when starting treatment with cannabis oil is 20g.
• The recommended monthly amount of cannabis when starting treatment with cannabis inflorescence is 20g. Determining the amount of cannabis product further along the treatment plan
• Work out the short-term daily requirements first • Switch product before increasing dose • the recommended dose should be taken 4 to 6 times a day at fixed intervals on a daily basis, usually in several inhalation/drops each time. • The titration process may take several months, and the patient may increase their dosage based on their medical condition until uniform relief is achieved. A titration protocol (depending on potency) of cannabis products
CBD RICH THC RICH Cannabis T0 T1 T3 T5 T10 T10 T15 T20 product C24 C20 C15 C10 C2 C10 C3 C4
20 20 20 20 20 20 20 20 30 30 30 30 30 30 30 30 40 40 40 40 40 40 40 40 50 50 50 50 50 50 50 50
60 60 60 60 60
Monthly cannabis cannabis Monthly amount (grams) amount
• Start at any of the boxes
• Treatment progresses in any direction of an arrow
• If the next treatment grade causes an undesired response, return to the previous amount, or to another starting point determined by the physician One rule to bind them all… One rule to bind them all… Go Slowwwwww…
start low… australian medical cannabis observatory Gotta’ start somewhere…
• 1mg / 10 kg body weight THC alone
• 1mg / 5 kg body weight THC-CBD
australian medical cannabis observatory Gotta’ start somewhere…
Weight Dose
70kg 2.5mg-5mg CBD/THC
70kg-100kg 5mg-10mg CBD/THC
Increase dose by 2.5mg dose until effective Example of a treatment diary Treatment Day Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 1 morning 1 morning 1 morning 1 morning … … … inhalation inhalation inhalation inhalation 1 evening 1 afternoon 1 afternoon inhalation inhalation inhalation 1 evening 1 evening inhalation inhalation
6 5 4 4 3 1 1 Pain Score
Did not Partially Partially Partially Partially Helped Helped Sleep help helped helped helped helped (7 hours) (7 hours) (2 hours) (3 hours) (3 hours) (4 hours) (5 hours) Partially Partially Partially Helped Helped Helped Helped Nausea helped helped helped Morning relief Morning relief Morning relief
Partially Partially Helped Helped Helped Helped Helped Appetite helped helped Especially in Especially in the morning the morning
None Dizziness Slight None None None None Negative Effects dizziness So, where are we going? So, where are we going? • Inevitable expansion of this area of medicine
australian medical cannabis observatory This won’t be easy for everyone… So, where are we going? • Inevitable expansion of this area of medicine
• Important to maintain differentiation between recreational and medicinal markets australian medical cannabis observatory In Summary…
• “There is no evidence”
• “It’s dangerous”
• “You can’t dose botanical products”
• “Opposition is purely scientific / medical” australian medical cannabis observatory In Summary…
• There is actually quite a lot of evidence, and growing
• Far less dangerous than many alternatives
• Of course you can dose botanical products
• Opposition is mostly economic, political australian medical cannabis observatory australian medical cannabis observatory