Medical Marihuana A paradigm delayed? Have you been run over by the Kuhn cycle?

How did cannabis disappear from medicine in the first place?

An overview of what we know about the medical potential of cannabis Gaylord Wardell MD (U of S,1978); FRCP(C) (U of S, 1988) FRCP Pain Medicine, 2016

Self-portrait Conflict of Interest Disclosure: Company-Supported Lectures FINANCIAL DISCLOSURE: Grants/Research Support:AHS,Purdue Pharma, Pfizer, Janssen Speakers Bureau/Honoraria:Valeant, Biovail, Lilly, Cannimed, Tweed Consulting Fees:none Other: None The impression that marihuana is a dangerous drug which must be carefully regulated is widespread, particularly in medical circles and governments.1

The vast majority of the public feel marihuana should be legalised for medicinal use.3

The majority of doctors in Canada do not prescribe medical marihuana despite it having been legal since 2001.1

As far back as 1969, the Le Dain Commission on the Non Medical Use of Drugs decries the number of Canadians incarcerated for drug related crimes and called for decriminalisation of possession of marihuana for personal use.2

Considering that, when taken as prescribed, there has never been a death from medical marihuana yet there are thousand of deaths annually in North America from NSAIDs, opioids, acetaminophen, antidepressants, anticonvulsants, tobacco and alcohol which are all widely used legally and illegally.4

Is the barrier erected against marihuana based on a possibly mistaken negative perception of cannabis in the medical community that is impeding a more useful paradigm? The body of historical literature supports a conclusion that cannabis, if not actually valuable, is not sufficiently harmful to be vilified as it has, and yet this conclusion has been only slowly accepted in the medical and policing community

Max Planck: A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grow up that is familiar with it. 1.By Jennifer Lee, CBNC News poll Posted: Jul 31, 2017 5:00 AM MT Last Updated: Jul 31, 2017 5:00 AM MT 2.Canadian Government Commission of Inquiry into the Non-Medical Use of Drugs. Information Canada. Gerald Ledain, 1969 3.Jun 30, 2016 - 7 in 10 Canadians support marihuana legalization: Nanos poll 4.Drug Overdose Deaths in the United States, 1999–2016 Holly Hedegaard, M.D., Margaret Warner, Ph.D., and Arialdi M. Miniño, M.P.H.CDC data 5. Cloning of type 1 cannabinoid receptor in Rana esculenta reveals differences between genomic sequence and cDNA Rosaria Meccariello1 , Rosanna Chianese2 , Gilda Cobellis2 , Riccardo Pierantoni2 and Silvia Fasano 6. The active chemical of cannabis is identified J Amer Chem Soc 86; 1646-7, 1964 7. National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: The current state of evidence and recommendations for research. Washington, DC: The National Academies Press. doi: 10.17226/24625. .8.The endocannabinoid signaling system: a potential target for next-generation therapeutics for alcoholism Balapal S. Basavarajappa Mini Rev Med Chem. 2007 Aug; 7(8): 769–779 The existence of a major signalling system, the endocannabinoids and its receptors, with major implications for medical therapeutics, has been known for over forty years.8 “Men occasionally stumble over the truth, but most of them pick them- The ligands have been identified.6 selves up and hurry off as if nothing The receptors have been cloned and mapped.5 ever happened!”

The potential for many medical benefits have been clearly delineated and much research has already been done.7

These are facts, yet in North America the research and potential medical application of cannabis and its elements has lagged far behind its potential.

WHY? Sir Winston Churchill LaGuardia Committee Report on Marijuana 1944

CONCLUSIONS 1. Under the influence of marihuana the basic personality structure of the individual does not change but some of the more superficial aspects of his behavior show alteration. 2. With the use of marihuana the individual experiences increased feelings of relaxation, disinhibition and self-confidence. 3. The new feeling of self-confidence induced by the drug expresses itself primarily through oral rather than through physical activity. There is some indication of a diminution in physical activity. LaGuardia Committee Report on Marijuana 1944

4. The disinhibition which results from the use of marihuana releases what is latent in the individual's thoughts and emotions but does not evoke responses which would be totally alien to him in his undrugged state. 5. Marihuana not only releases pleasant reactions but also feelings of anxiety. 6. Individuals with a limited capacity for effective experience and who have difficulty in making social contacts are more likely to resort to marihuana than those more capable of outgoing responses. Cannabis was legal medicine from the initial colonization until 1937 only being removed from the US Pharmacopeia in 1941

HOW DID IT BECOME ILLEGAL?? How did we go from this: To this?

SCHEDULE 1 (CLASS I) DRUGS are illegal because they have high abuse potential, no medical use, and severe safety concerns; for example, narcotics such as Heroin, LSD, and cocaine. Marijuana is also included as a Class 1 drug*

• *These are American FDA classes, although they are different in Canada, where medical cannabis is legal, for most of the 20th Century Canada followed the American lead on illegality. Cannabis cannot legally cross the border to the USA - Attorney General John Mitchell of the Nixon administration placed marijuana in this category in 1972 The Indian Hemp Drugs Commission 1893-1894

• The house of commons of the United Kingdom was concerned with the effects of hemp drugs in the province of Bengal, India • 490 pages report • 2000 witnesses from military officers to missionaries in 30 cities across India • The commission has come to the conclusion that the moderate use of hemp drugs is practically attended by no evil results at all Marijuana on Trial: The Panama Canal Zone Report 1925

Concern among army officers about marijuana’s effects on discipline and morale led to the issuing of Army circular No. 5 on January 20, 1923. The circular banned the possession and use of marijuana by army soldiers in the Canal Zone and subjected violators to a court-martial and dishonorable discharge. By April of 1925, a joint civilian and military committee was formed to study the effects of marijuana on users and to re-evaluate the logic of Circular No. 5. The conclusions of the report were that the deleterious effects of marijuana had been exaggerated, and it recommended that no restrictions be placed on the use of the drug. 1. 1894 Indian Hemp Drugs Commission, "Report of the Indian Hemp Drugs Commission", Simla, India: Government Central Printing Office "The commission has come to the conclusion that the moderate use of hemp drugs is practically attended by no evil results at all." 2. 1925 Canal Zone Committee, "The Panama Canal Zone Military Investigations" "The influence of [marijuana]... has apparently been greatly exaggerated... There is no evidence... that it has any appreciably deleterious influence on the individual using it.“ 3. 1944 Mayor's Committee on Marihuana, "The La Guardia Commission Report“ 4. 1969 Advisory Committee on Drug Dependence, "Cannabis", London: Her Majesty's Stationery Office. 5. 1970 Canadian Government Commission of Inquiry, "The Non-Medical Use of Drugs", Ottawa, Canada: Information Canada. (a.k.a "Le Dain Commission") "Since cannabis is clearly not a narcotic we recommend that the control of cannabis be removed from the Narcotic Control Act... The Commission is of the opinion that no one should be liable to imprisonment for simple possession." 6. 1972 National Commission of Marihuana and Drug Abuse, "Marijuana: A Signal of Misunderstanding, Washington, D.C.: U.S. Government Printing Office. "Marihuana's relative potential for harm to the vast majority of individual users and its actual impact on society does not justify a social policy designed to seek out and firmly punish those who use it... Existing social and legal policy is out of proportion to the individual and social harm engendered by the drug." 7. 1972 Werkgroep Verdovende Middelen, "Background and Risks of Drug Use", The Hague: Staatsuitgeverij. 8. 1977 Senate Standing Committee on Social Welfare, "Drug Problems in Austrailia- An Intoxicated Society?", Canberra: Austrailian Commonwealth Government Printing Office. "Legal controls [should] not [be] of such a nature as to... cause more social damage than use of the drug... Cannabis legislation should be enacted that recognizes the significant differences between... narcotics and cannabis in their health effects... Possession of marijuana for personal use should no longer be a criminal offence." 9. 1982 National Research Council, "An Analysis of Marijuana Policy", Washington D.C.: National Academy Press. "The advantages of a policy of regulation include... the savings in economic and social costs of law enforcement... better controls over the quality and safety of the product, and, possibly, increased credibility of warnings about risks." 10. 1994 McDonald D., et al., "Legislative Options for Cannabis in Australia", Report on the National Task Force on Cannabis", Canberra: Australian Government Publishing Service. "Australian experiences more harm... from maintaining cannabis prohibition policy than it experiences from the use of the drug... We conclude that cannabis law reform is required in this country." 11. 1995 Ministry of Health, Welfare, and Sport, "Drug Policy in the Netherlands: Continuity and Change", The Netherlands. "It has been demonstrated the more or less free sale of... [marijuana] for personal use in the Netherlands has not given rise to levels of use significantly higher than in countries which pursue a highly repressive policy... Dutch policy on drugs over the last twenty years... can be considered to have been successful." 12. 2002 Senate Special Committe on Illegal Drugs, "Cannabis: Our Position for a Canadian Public Policy Summary Report", Ottawa, Canada. "Scientific evidence overwhelmingly indicates that cannabis is substantially less harmful than alcohol and should be treated not as a criminal issue but as a social and public health issue." The body of historical literature supports a summation that cannabis, if not actually valuable, is not sufficiently harmful to be vilified as it has, and yet this reality has been only slowly accepted in the medical and policing community

"The book" was The Structure of Scientific Revolutions(First Edition, 1962), which may be the most influential treatise ever written on how science does (or does not) proceed. It is notable for having spawned the trendy term "paradigm." It also fomented the …. idea that personalities and politics play a large role in science.

•By John Horgan on May 23, 2012 Scientific American

Max Planck: A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grow up that is familiar with it. the …. idea that personalities and politics play a large role in science Cannabeaver, eh

More likely, cannabis was added to the list because of Canadian involvement in international conferences where it was discussed. According to one government official, cannabis was outlawed after the Director of the Federal Division of Narcotic Control returned League of Nations meetings where the international control of the drug was broached. Cannabis did not begin to attract official attention in Canada until the latter 1930s.The first seizure of cannabis by Canadian police was not until 1937. Between 1946 and 1961, cannabis accounted for 2% of all drug arrests in Canada.

Cannabis was virtually unheard of in the 1920s so why the pressing need to make it illegal? Yes there was the close connection to the political pressure from the USA, but could there have been a more local cause for all the concern? Janey Canuck AKA Emily Murphy Emily Murphy’s The Black Candle (1922), the notorious, influential book that first defined drugs as a social problem in Canada, introduced the public to their varieties and effects, and directly contributed to the addition of marijuana to the Restricted List in 1923 One of their earliest and most influential promoters was an Edmonton woman who in 1920 wrote exposes for Maclean's about the illicit drug trade. She called herself Janey Canuck, and it was good old Janey who first warned Canadians about "marahuana." Seven years later, Canada outlawed its use….and many of her "original proposals are still reflected in our narcotics legislation."

Janey urged stiffer jail sentences for drug offenders, healthy doses of the lash, and if they were aliens, instant deportation. She was not a nice person… her writing was sensationalist, fable-ridden and exploitive of "popular racial bias." Yes indeed. "She created a series of women-seducing villains, primarily non-white and non-Christian, who threatened the Anglo-Saxon way of life."

While explaining the motive behind the drug trade, Janey declared, "It is claimed, but with what truth we cannot say, that there is a well-defined propaganda among the aliens of color to bring about the degeneration of the white race." Another thing she apparently could not say was who The secret shame of Maclean’s made the claim. As with many early cannabis prohibitionists, racism played a huge role. A history of moral panic about marijuana in Canada by Colby Cosh Sep 23, 2010

Canada: the Real Janey Canuck Nartional Post. 2000 1923: Cannabis was deemed illegal in Canada in 1923, after the Narcotics Drug Act Amendment Bill introduced the Act to Prohibit the Improper Use of Opium and Other Drugs, adding cannabis, in addition to opium, cocaine and morphine. 1937: The first marijuana seizure was made by Canadian law enforcement. The same year the Marihuana Tax Act ended any hope of legal use in the USA

As we can see there was not much interest in Canada surrounding cannabis but Canadians are heavily influenced by events immediately south of our border. The collateral effects of the Eighteen Amendment which brought PROHIBITION of recreational alcohol to America from 1920 to 1933 plays a role in the cannabis prohibition to great to cover here America’s creation of the ‘marihuana menace’ paradigm

1. Social locus- the illegal immigration of millions of Mexican running from the Mexican Civil War who used the formerly innocent herb

2. Powerful police, publicists and politicians who were willing to be very malleable with the truth to produce a climate where the immigrant was vilified(so few white Americans were even aware that cannabis and the evil marihuana of the Mexicans was the same that it was of no consequence)

3. A single powerful advocate, in the name of Harry J. Anslinger who combined these factors to further his political aspirations. A single powerful advocate in the person of Harry J. Anslinger The Pure Food and Drug Act of 1906

Linked cannabis, a widely used herbal remedy of the previous century with cocaine, alcohol and heroin as a dangerous ‘drug’

The connection would persist into the next century The Development of the Harrison Narcotics Tax Act of 1914

As a Tax Act this put illegal drugs under the control of the tax collectors for the next 54 years until reorganisation in 1968.

Tax collectors, not social workers or healthcare professionals, directed enforcement of drug policy in the USA with somewhat predictable results. This would later include cannabis Starting at the end of 1934, Anslinger vigorously employed the image of the marihuana menace in his campaign (Federal Bureau of Narcotics) to encourage the states for its prohibition.

In the summer of 1937, the states got their wish and the Marijuana Tax Act was enacted.

Penalties for marijuana were drastically reduced after white, upper middle class college students began using the drug in large numbers in the 1960s and politicians could see that the negative behavior associated with the drug did not translate when their children became users. A single powerful advocate, in the name of Harry J. Anslinger

He was the first commissioner of the Federal Bureau of Narcotics, which laid the ground work for the modern-day DEA, and the first architect of the war on drugs.

Anslinger first claimed that the drug could cause psychosis and eventually insanity. In a radio address, he stated young people are “slaves to this narcotic, continuing addiction until they deteriorate mentally, become insane, turn to violent crime and murder.”

The second component to Anslinger’s strategy was racial. He claimed that black people and Latinos were the primary users of marijuana, and it made them forget their place in the fabric of American society. He even went so far as to argue that jazz musicians were creating “Satanic” music all thanks to the influence of pot. Anslinger’s use of ‘evidence based medicine’ in the creation of the ‘marihuana menace’ that resulted in the prohibition of marihuana

What evidence did Harry Anslinger have? It turns out at this time he wrote to the 30 leading scientists on this subject, asking if cannabis was dangerous, and if there should be a ban.

Twenty-nine wrote back and said no.

Anslinger picked out the one scientist who said yes, and presented him to the world. The press — obsessed with Victor Licata’s axe* — cheered them on.

Chasing The Scream: The First and Last Days of the War on Drugs Johann Hari *Then we have the case of a young boy in Florida. The story runs as follows: "A young boy who had become addicted to smoking marihuana cigarettes, in a fit of frenzy because, as he stated while still under the marihuana influence, a number of people were trying to cut off his arms and legs, seized an axe and killed his father, mother, two brothers and a sister, wiping out the entire family except himself." --- Mr. Anslinger 1937 Congressional Testimony

Anslinger’s now famous GORE FILE of 200 stories, of which this is the most widely cited, crediting marihuana with causing horrific violent crimes have been shown to be unsubstantiated. * *HARRY ANSLINGERS GORE FILE: Starting around 1934 the Federal Government (specifically the Federal Bureau or Narcotics) began and then orchestrated a mass hysteria campaign against the Medical Marihuana plant. Complete with what we now term, “bumper sticker” slogans such as, “Marihuana - The Assassin of Youth,” or “Marihuana - The Killer Drug. ”

•That there is no evidence (physical or otherwise) that Victor Licata had ever even tried Marihuana let alone be classified as a "Marihuana Addict", as claimed by the police. We have been able to trace the source of this rumor back to Chief Detective W.D. Bush and have shown that he was less than an honest individual about the facts dealing with this case. Additionally, Victor Licata himself (to his dying day) refuted the story, claiming that he had never used it. And (granted) people do lie, logic and reason would dictate that the lie would have gone in the other direction. Once more there simply is no physical evidence to back up this claim.

•That there was NO MARIHUANA found in the Licata house. And as we have identified the source of this rumor and have shown that he was less than an honest individual, it can be stated that any such reports were false. The Vicious Myth Behind America’s Ban on Marijuana BY JOHANN HARI FEBRUARY 19, 2016 Haunted Ybor City;Deborah Frethem;Arcadia Publishing, Sep. 23, 2014 - Body, Mind & Spirit - 128 pages

The Marihuana Tax Act of 1937

Dr. William Woodward with the legislative counsel representing the American Medical Association (AMA), complained, “We cannot understand yet, Mr. Chairman, why this bill should have been prepared in secret for two years without any intimation, even, to the [medical] profession, that it was being prepared.”

Dr. Woodward pointed out that the medical and hemp industries had been blindsided by the bill because it used the term marihuana in the title instead of cannabis.

“The term ‘marihuana’ is a mongrel word that has crept into this country over the Mexican border and has no general meaning, except as it relates to the use of cannabis preparations for smoking,” the doctor explained. “It is not recognized in medicine, and hardly recognized even in the Treasury Department. Marihuana is not the correct term. It was the use of the term ‘marihuana’ rather than the use of the term ‘cannabis’ or the use of the term ‘Indian hemp’ that was responsible, as you realized probably, a day or two ago, for the failure of the dealers in Indian hemp seed to connect up this bill with their business until rather late in the day.” The Marihuana Tax Act of 1937

When the legislation, drafted by Anslinger, was presented on the floor of the House for a vote, a representative from upstate New York asked, “Mr. Speaker, what is this bill about?”

The Speaker replied, “I don’t know. It has something to do with a thing called marijuana. I think it’s a narcotic of some kind.”

The New York representative queried, “Mr. Speaker, does the American Medical Association support this bill?” A member of the hearing committee interrupted and replied, “Their Doctor Wentworth(WOODWARD) [sic] came down here. They support this bill one hundred percent.”

And thus, with that lie—and despite the efforts of Woodward (one of only two medical doctors to testify at the committee hearings) and the actual opposition of the American Medical Association—the U.S. Congress passed the Marijuana Tax Act of 1937 in early August The cultivation and possession of cannabis and hemp has been illegal in the United States ever since It was not until 1941 that it was realised that CANNABIS was indeed identical to MARIHUANA and was now illegal and had to be removed from the United States Pharmacopeia

Anslinger was also a liar. As the drug war got going in the early 20th century, the bureau published surveys showing its efforts to combat drug use had led to dramatic declines over the decade of the 1920s. But drug historian David Courtwright, through a Freedom of Information Act request, got his hands on the actual surveys and found the data to have been fabricated. He also found a private memo from Anslinger admitting the numbers were made up. Nevertheless, Anslinger used that success to argue for an expansion of the drug war to weed in 1937. (The incident is covered in the book This Is Your Country On Drugs, by HuffPost's Ryan Grim.)

Evidence for the pervasive paradigm of the ‘marihuana menace’ is widespread and encourage you to do your own research THE BASIC SCIENCE OF CANNABIS

Chuck Rosenberg, acting head of the DEA, explained the decision to keep marijuana as a Schedule I drug was based more “on whether marijuana, as determined by the FDA, is a safe and effective medicine." Regulations have prevented US researchers from answering this question over the last several decades. As written in a recent New York Times editorial, "the government itself has made it impossible to do the kinds of trials and studies that could produce the evidence that would justify changing the drug's classification."

The all too often used argument that ‘there is no evidence’ has been artificially created by the DEAs Schedule One designation of cannabis-NIDA(National Institute for Drug Abuse) supported only studies to show harm or lack of efficacy- this talk will avoid duelling studies where the freedom to research cannabis has been highly controlled THE BASIC SCIENCE OF CANNABIS

We are focusing on the basic science and history of cannabis as the clinical research on cannabis in Canada and United States has been so seriously biased by Scheduling THE BASIC SCIENCE OF CANNABIS

Tetrahydrocannabinol – THC Cannabidiol – CBD The two principal active cannabinols there are over one hundred and forty in Raphael Mechoulam’s Israel laboratory: in 1963 for CBD and in 1964 for Δ9-THC, when it was first isolated from cannabis. It was also in Mechoulam's laboratory, in 1965, that (±)-Δ9- THC and (±)-CBD were first synthesized

Br J Pharmacol 2006 Jan; 147(Suppl 1): S163–S171. Published online 2006 Jan 9. doi: 10.1038/sj.bjp. THE BASIC SCIENCE OF CANNBABIS CB1 and CB2 These receptors are the sites of the action of THC In the mid 1980s the CB1 and CB2 receptors were proven to exist and by the mid 1990s these receptors had been cloned.(Howlett,Devane,Bonner,Gerard,Munroe)

Br J Pharmacol 2006 Jan; 147(Suppl 1): S163–S171. Published online 2006 Jan 9. doi: 10.1038/sj.bjp.0706406 THE BASIC SCIENCE OF CANNABIS THE BASIC SCIENCE OF CANNABIS THE BASIC SCIENCE OF CANNABIS

With the receptors identified and plant cannabinoids known for many years the search for endocannabinoids intensified

It was Devane, in Mechoulam’s lab in Israel along with Howlett who have led this research successfully in the 1990s ‘Anand’ from the Sanskrit for ‘bliss’ This is a large and widespread signalling system so its role in clinical medicine has very significant potential

THE BASIC SCIENCE OF CANNABIS Where do the cannabinoids exert their effects? THE BASIC SCIENCE OF CANNABIS PPARs Peroxisome proliferator activated receptors (PPARs) are a group of three nuclear receptors—PPAR- alpha, PPAR-gamma, and PPAR-delta (the latter is not yet well-characterized). PPARs are triggered by hormones, endogenous fatty acids, and various nutritional compounds. When activated, PPARs bind to certain segments of DNA to promote or prevent transcription of specific genes.

Many of the genes regulated by PPARs are involved in energy homeostasis, lipid uptake and metabolism, insulin sensitivity, and other metabolic functions. Big Pharma recognizes the importance of these nuclear receptors. Thus far, two classes of pharmaceutical PPAR activators—fibrates and thiazolidinediones—have been approved by the U.S. Food and Drug Administration. Saoirse Elizabeth O’Sullivan British Journal of Pharmacology (2016) 173 1899–1910 THE BASIC SCIENCE OF CANNABIS PPARs

Physiological responses to cannabinoids mediated by PPARs Reward Memory and cognition Analgesia Neuroprotection Anti-tumour effects of cannabinoids Cardiovascular system

Saoirse Elizabeth O’Sullivan British Journal of Pharmacology (2016) 173 1899–1910 THE BASIC SCIENCE OF CANNABIS THE BASIC SCIENCE OF CANNABIS TRP V

Transient receptor potential receptors are best known for the release of Substance P and calcitonin gene related peptide(CGRP) in response to CAPSAICIN from hot peppers

Phyto cannabinoids, endogenous cannabinoids and synthetic cannabinoids can reduce or increase the output of these receptors with significant medical potential

Acta Physiol (Oxf). 2012 Feb;204(2):255-66. doi: 10.1111/j.1748-1716.2011.02338.x. Epub 2011 Aug 12. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. De Petrocellis L ,Orlando P, Moriello AS, Aviello G,Stott C, Izzo AA,,Di Marzo V THE BASIC SCIENCE OF CANNABIS GPR55

This g protein coupled receptor is involved in bone formation and neurogenic inflammation due to interaction with endogenous and endogenous cannabinoids. It is neither CB1 or CB2 but is agonised by THC and antagonised by CBD.

Atypical Responsiveness of the Orphan Receptor GPR55 to Cannabinoid Ligands* 1.Ankur Kapur, Pingwei Zhao‡, Haleli Sharir Yushi Bai, Marc G. Caron§,Larry S. Barak and 2.Mary E. Abood From the ‡Department of Anatomy and Cell Biology and Center for Substance Abuse Research, Temple University, Philadelphia, Pennsylvania 19140 The §Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710 July, 2009 THE BASIC SCIENCE OF CANNABIS Terpenes

Terpenes are derived biosynthetically from units of isoprene, which has the molecular formula C5H8. The basic molecular formula of terpenes are multiples of that, (C5H8)n where n is the number of linked isoprene units. This is called the biogenetic isoprene rule or the C5 rule. In 1953, Leopold Ružička discovered that the isoprene units may be linked together "head to tail" to form linear chains or they may be arranged to form rings.

Terpenes play a vital role in the plant kingdom; they deter insect predation, protect plants from environmental stresses, and act as building blocks for more complex molecules, such as cannabinoids. Many terpenes act synergistically with other varieties of terpenes, and some either catalyze or inhibit formation of different compounds within a plant. Understanding how terpenes function allows scientists to manipulate cannabinoids to desired ratios. Cannabis enthusiasts use the term ‘Entourage effect’ to postulate that the terpenes and cannabinoids creat a sum greater then the parts.

Still, there is no hard evidence that the ‘entourage effect’ is real. Double-blind clinical trials, the gold standard for research studies in medicine, have never been conducted to investigate the effects of marijuana’s terpenes or its cannabinoids other than THC. “With marijuana, most of what you’re dealing with is anecdotal evidence,” Scientific American April, 2017 THE BASIC SCIENCE OF CANNABIS Four types of cannabinoids 1. Plant cannabinoids(phytocannabinoids) 1. Tetrahydrocannabinol(THC) the psychoactive component of cannabis 2. Cannabidiol-non psychoactive and the main cannabinol in hemp oil

2. Endogenous cannabinoids 1. 2AG 2. Anandamide

3. Synthetic cannabinoids 1. Nabilone(Cesamet) very similar action to THC at CB1 and CB2 receptors but about 5-6 times more [potent 2. Dronabinol-an exact synthetic copy of THC

4. Nabiximols(Sativex). GW Pharma-natural but formulated into a peppermint flavoured buccal spray containing 2.7 mg of THC and 2.5 mg of CBD per spray THE BASIC SCIENCE OF CANNABIS Synthetic cannabinoids

Marinol-1985-synthetic version of THC with obviously identical actions and Sativex is not synthetic-it is natural kinetics-Class 3, however! and supplied in a buccal spray with a peppermint flavour Nabilone-synthetic with an action close to THC but about five times more Each spray-100 microliter or 0.1 ml potent-it is not synthetic THC contains 2.7 mg of THC and 2.5 mg of CBD Syndros-marinol in a liquid 5mg/ml THE BASIC SCIENCE OF CANNABIS

FDA committee recommends cannabis-based drug Product, derived from natural cannabis, doesn't contain high-inducing compound by Maggie Fox / Apr.19.2018 / 11:51 AM ET / Updated Apr.20.2018 / 5:48 AM ET

“The results from ….three studies provide substantial evidence of the effectiveness of CBD for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome (LGS and DS),” the FDA said in briefing documents given to the advisory committee ahead of Thursday’s meeting.

1. Devinsky O, Cross JH, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017; 376;2011-20. 2. Berkovic, SF. Editorial: Cannabinoids for epilepsy – real data, at last. N Engl J Med 2017; 376;2075-76. CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS There is “conclusive or substantial evidence” that marijuana or related compounds can effectively treat chronic pain, nausea caused by chemotherapy treatment for cancer, and spasticity caused by multiple sclerosis, according to a report published …… by the National Academies of Sciences, Engineering, and Medicine. CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS

••Cannabis use was associated with 64% lower opioid use in patients with chronic pain. ••Cannabis use was associated with better quality of life in patients with chronic pain. ••Cannabis use was associated with fewer medication side effects and medications used.

Medical Cannabis Use Is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain Kevin F. Boehnke; Evangelos Litinas Daniel J. Clauw DOI: https://doi.org/10.1016/j.jpain.2016.03.002 CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS

Opioid-related mortality increased by 15.6% from 2014 to 2015 and increased almost 320% between 2000 and 2015. Recent research finds that the use of all pain medications (opioid and nonopioid collectively) decreases in Medicare Part D and Medicaid populations when states approve medical cannabis laws (MCLs). The association between MCLs and opioid prescriptions is not well understood. Conclusions and Relevance Medical cannabis laws are associated with significant reductions in opioid prescribing in the Medicare Part D population. This finding was particularly strong in states that permit dispensaries, and for reductions in hydrocodone and morphine prescriptions. Association Between US State Medical Cannabis Laws and Opioid Prescribing in the Medicare Part D Population Ashley C. Bradford, BA1; W. David Bradford, PhD1; Amanda Abraham et al;Grace Bagwell Adams, PhD2 Author Affiliations JAMA Intern Med. Published online April 2, 2018. doi:10.1001/jamainternmed.2018.0266 CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta- analysis of pre-clinical studies indicated that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9- THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the

ED50 of morphine alone. In addition, the ED50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the

ED50 of codeine alone.

Neuropsychopharmacology. 2017 Aug;42(9):1752-1765. doi: 10.1038/npp.2017.51. Epub 2017 Mar 22. Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis. Nielsen S, Sabioni Ptrigo, JM Ware, MA, Betz-Stablein BD, Murnion B, Lintzeris N’ Khor KE’ Farrell M, Smith A, Le Foll B. CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS

An updated systematic review of randomized controlled trials examining cannabinoids in the treatment of chronic non-cancer pain was conducted according to PRISMA guidelines for systematic reviews reporting on health care outcomes. Eleven trials published since our last review met inclusion criteria. The quality of the trials was excellent. Seven of the trials demonstrated a significant analgesic effect. Several trials also demonstrated improvement in secondary outcomes (e.g., sleep, muscle stiffness and spasticity). Adverse effects most frequently reported such as fatigue and dizziness were mild to moderate in severity and generally well tolerated. This review adds further support that currently available cannabinoids are safe, modestly effective analgesics that provide a reasonable therapeutic option in the management of chronic non-cancer pain.

J Neuroimmune Pharmacol.2015 Jun;10(2):293-301. doi: 10.1007/s11481-015-9600-6. Epub 2015 Mar 22. Cannabinoids for the Treatment of Chronic Non-Cancer Pain: An Updated Systematic Review of Randomized Controlled Trials. Lynch ME, Ware MA CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS

Strong in vitro(laboratory) evidence of a cannabinoid effect on human cancer cells

There are many claims made by medical cannabis activists, BUT such claims need substantiating with clinical studies in real patients

This is long overdue and has been inhibited by the ‘marihuana menace” paradigm which has kept the plant as Schedule ONE

The FDA and doctors cannot continue with the ‘no evidence’ retort until research is unfettered and has shown no benefit CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS

meta-analysis of 34 in vitro and in vivo studies of cannabinoids in gliomas reported that all but one study confirmed that cannabinoids selectively kill tumor cells

Human/Clinical Studies the review of the published meta-analyses, the National Academies of Sciences, Engineering and Medicine (NASEM) report concluded that there was moderate evidence of no statistical association between Cannabis smoking and the incidence of lung cancer Cannabis and Cannabinoids (PDQ®)–Health Professional Version National Cancer Institute at the National Institutes of Health •Updated: November 30, 2017 CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS

Curr Oncol 2016 Mar; 23(Suppl 2): S23–S32. Published online 2016 Mar 16. doi: 10.3747/co.23.3080 Anticancer mechanisms of cannabinoids G. Velasco, PhD,*†‡ C. Sánchez, PhD,*§ and M. Guzmán, PhD*†‖ CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS

HMEC-1 is the first immortalized human microvascular endothelial cell line that retains the morphologic, phenotypic, and functional characteristics of normal human microvascular endothelial cells.

J Invest Dermatol. 1992 Dec;99(6):683-90. HMEC-1: establishment of an immortalized human microvascular endothelial cell line. Ades EW, Candal FJ, Swerlick RA, George VG, Summers S, Bosse DC, Lawley TJ CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS CLINICAL APPLICATIONS OF CANNABIS AND CANNABINOIDS

According to the American FDA and the Canadian Medical Association, there are none

Submission to the House of Commons Standing Committee on Health Aug.18, 2017 ; The Canadian Medical Association The value of the plant Thank-you for your valuable time. May needless suffering become your enemy Further Reading

Seeing through the Smoke: The Origins of Marihuana Prohibition in the United States by Michael F. Linden, 2015 A thesis submitted to the faculty of Wesleyan University

Smoke Signals- A Social History of Marijuana- Medical, Recreational and Scientific

The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research The National Academies of Sciences, Engineering and Medicine 2017

The Structure of Scientific Revolutions (1962; second edition 1970; third edition 1996; fourth edition 2012) is a book about the history of science by the philosopher Thomas S. Kuhn