Mary's Prime Time Issue #2

MARY’S PRIME TIME

Coverage and Commentary on the Top Cannabis Conferences • Issue 2 • 2018

The Golden Age of Cannabis Research?

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s this the golden age of cannabis research? Around the globe there are countless, ongoing research projects involving cannabis and its many components, particularly cannabidiol (CBD). A simple search on pubmed.gov (the database of the U.S. National Library of Medicine) demonstrates the dramatic rise of published research papers pertaining to cannabis in the 21st Century.

Despite a growing mountain of published data demonstrating the safety and efficacy of cannabis in treating multiple ailments, the U.S. Federal government demonstrates a mind-boggling obstinacy when it comes to the plant. It refuses to move cannabis out of Schedule 1, the most prohibitive of all U.S. drug schedules. And the reason is, they will repeat over and over again, “there is not enough research.” Poppycock!

The accompanying chart, compiled from data at the National Library of Medicine, demonstrates the explosion of published cannabis research in the past fifteen years. And with each year there is also a growing number of cannabis conferences. In 2017 the two crown jewels of cannabis research conferences convened: ICRS in Montreal and IACM in Cologne. These two organizations have been presenting cannabis research for many years. ICRS became officially organized in 1992 but held informal meetings as far back as 1970. IACM first organized in 2000.

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This issue of Mary’s Prime Time is focused on these two exciting scientific conferences. The ongoing exploration of the cannabis plant is revealing an amazing assortment of potential therapeutic applications and future generations may indeed look back on this time as the Golden Age of Cannabis Research. 

Conference Facts

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Sponsor: International Cannabis Research Society (ICRS) Dates: June 23-26, 2017 Venue: Montreal, Quebec, Canada Attendees: 350 Meeting Background: The ICRS meets annually at various venues around the globe. The meeting is highly technical with most presentations focusing on scientific discovery as opposed to clinical application. Mary’s Prime Time is grateful to Martin A. Lee of Project CBD for granting permission to use his summary of the 2017 ICRS meeting.

Next Meeting: June 30th - July 5th, 2017, Leiden, The Netherlands

Sponsor: International Association for Cannabinoid Medicines (IACM) Dates: September 29-30, 2017 Venue: Cologne, Germany Attendees: 348 Meeting Background: The IACM meets every two years with most conferences held in Europe. The focus of IACM is more clinical than that of the ICRS. The full abstract book from the conference can be found at: https://www. cannabis-med.org/nis/data/file/abstractbook_2017.pdf Next Meeting: To be announced

ICRS 2017: A Report from Montreal by

Martin A. Lee

Originally published at Project CBD , July 24, 2017. Gratefully used with permission

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uring the last week of June, more than 400 scientists from 25 countries met in Montreal for the 27th annual symposium of the International Cannabinoid Research Society (ICRS). Several presentations and posters showcased new findings about cannabidiol (CBD), the non-euphoric component of the cannabis plant that is transforming the medical marijuana landscape. In her Young Investigator Award Presentation, Saoirse O’Sullivan, associate professor at the University of Nottingham in the United Kingdom, discussed the cardiovascular effects of cannabidiol: “CBD causes both acute and time dependent vasorelaxation of rat and human arteries … and can improve endothelial function and vasodilator responses in a rat model of type 2 diabetes.”

Moreover, a single dose of CBD was found to decrease “resting blood pressure and the blood pressure response to stress.”

Other studies indicate that CBD limits brain damage in animal models of stroke. “Collectively, these data suggest that CBD is a compound of interest in the cardiovascular system and in cardiovascular disorders, which need to be tested in relevant patient groups,” O’Sullivan concluded.

A poster by Dr. Paula B. Dall’Stella, a neuro-oncologist with Sirio Libanes Hospital in San Paulo, Brazil, documented the antitumoral effects of CBD in two patients with Glioblastoma Multiforme (brain cancer) that were resistant to other therapies.

Mary’s Prime Time Published periodically by Mary’s Medicinals Editor-in-Chief: Alice O’Leary Randall alice@marysmedicinals.com Contributor: Justin Kander Design: Jesica Clark Editorial Assistance: Eloise Theisen

MarysMedicinals.com

Special thanks to Project CBD for permission to use Martin A. Lee’s report on the ICRS meeting.

Published by Mary’s Medicinals, Denver, CO Copyright (c) 2018 - All rights reserved This publication is solely for educational purposes and is not intended to substitute for the medical advice of a treating physician.

Medicine and cannabis research is an ever-changing science.

Therefore, the editor, contributors and publisher do not accept responsibility in the event of negative consequences incurred as a result of the information presented in Mary’s Prime Time. We do not claim this information is necessarily accurate by rigid scientific and regulatory standards applied for medical treatment. No warranty, expressed or implied, is furnished with respect to the material contained in this publication. Readers are encouraged to consult with personal physicians with respect to treatment of any medical condition.

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Mary’s Prime Time • Issue 2 • 2018

Before and after MRI scans showed “a marked remission … not commonly observed in patients only treated with conventional modalities … that could impact survival.”

Several presentations focused on CBD and treatment-resistant epilepsy. Dr. Fabricio A. Pamplona, scientific director of Entourage Phytolab in San Paulo, Brazil, compared the efficacy of a purified CBD isolate to a whole plant CBD-rich oil extract.

Pamplona found the whole plant extract to be a superior option with higher potency and fewer adverse side effects than singlemolecule CBD: “There were more reports of ‘improvement in seizures frequency’ in CBD-enriched extract compared to purified CBD,” a result that he attributed to the “additional compounds available in extracts (other than CBD) that may interact synergistically.”

Israeli researchers at the Technion Institute in Haifa found that “not all high CBD extracts have the same anticonvulsant ability.” The Israelis noted that “the terpenoid content in the cannabis extracts are important for the anticonvulsant effect.”

(Terpenoids are derived from terpenes, the aromatic botanical compounds that endow cannabis with a unique smell and confer specific medicinal effects.) “Not all cannabis extracts will be useful as a treatment for epilepsy,” the Technion researchers concluded, adding: “[T]he exact cannabinoid and terpenoid profiles are needed to evaluate the potential anticonvulsant properties of a cannabis extract.”

Another poster drew attention to the fact that daily use of CBDrich cannabis oil extracts may lead to a positive THC finding in a drug test, a concern for many U.S. patients in so-called “CBD-only states” that have legalized CBD but not the whole plant. Unfortunately, this poster resurrected the thoroughly discredited (and financially motivated) theory that CBD may convert to THC in the stomach. A more likely explanation is that any whole cannabis plant extract that includes even a small amount of THC could generate a positive result from a drug test. Given the unregulated CBD products that proliferate online, it’s not surprising that some “CBD” oils contain higher THC concentrations than advertised.

Other scientists probed CBD’s mechanism of action with respect to nausea, neuropathic pain, anxiety, and other mood disorders. Researchers at McGill University in Montreal found that analgesic effects of acute and chronic CBD treatment are mediated by the serotonin 5HT1a receptor, but this is not the case for CBD’s antidepressant effects, which seem to be regulated via other molecular pathways.

The complex role of the 5HT1a receptor with respect to CBD’s therapeutic properties was addressed in a poster by Aidan J. Hampson and his colleagues at the National Institute of Drug Abuse. It was Hampson’s work, published in 1998, that formed that basis for the U.S. government’s patent on the antioxidant and neuroprotectant properties of cannabinoids (both THC ICRS 2017: A Report from

and CBD). More recently, Hampson has shown that the anxietyrelieving effect of CBD can be blocked in vivo (in a living animal) by a 5HT1a antagonist, indicating that this receptor is in part responsible for mediating the anxiolytic effects of cannabidiol.

Curiously, Hampson’s current data suggests that in addition to binding directly to 5HT1a, cannabidiol may also act as a positive allosteric modulator of 5HT1a – meaning that CBD can alter the functionality of this receptor (and other serotonin receptor subtypes) in such a way as to enhance its binding efficiency with the endogenous serotonin neurotransmitter. In other words, CBD may actually magnify the effect of serotonin, in addition to directly activating the 5HT1a receptor.

reducing effects: “[C]hronic cannabis use is associated with a blunted stress response and a reduced reliance on top-down attentional control that does not cause overall cognitive performance to suffer.”

• Addiction: Vincenzo Di Marzo, a leading cannabinoid scientist at the Institute of Biomolecular Chemistry in Naples, Italy, gave a fascinating presentation on the cessation of nicotine addiction among cigarette smokers who suffer a traumatic brain injury. Di Marzo identified an endogenous lipid molecule, N-oleoyol-glycine (OlGly), which activates a receptor on the membrane of the

Scientists at the University of Louisville School of Medicine in Kentucky have identified two new molecular targets of CBD – the receptors designated “GPR3” and “GPR6.” (GPR refers to G-coupled protein receptor, the family of receptors that includes cannabinoid, opioid, and several serotonin receptor subtypes.) GPR3 and GPR6 are both known as “orphan receptors” because the principal endogenous compounds that bind to these receptors have yet to be identified.

Some of the potential therapeutic effects of CBD for Alzheimer’s disease, Parkinson’s disease and schizophrenia may be mediated by GPR3 and GPR6.

Amyloid beta plaque and tau protein tangles in the brain are hallmarks of Alzheimer’s dementia. Tim Karl from the Western Sydney University School of Medicine in Australia elaborated on CBD’s therapeutic potential for this neurodegenerative brain disease: “The phytocannabinoid cannabidiol possesses antioxidant, anti-inflammatory and neuroprotective properties and prevents amyloid beta-induced neuroinflammation, and tau hyperphosphorylation in vitro. CBD also reverses cognitive deficits of pharmacological amyloid beta models. Thus, CBD may offer therapeutic value for Alzheimer’s disease.”

Another receptor, known as GPR55, is inhibited by CBD. This is significant because preclinical research has linked GPR55 activation to several aberrant conditions, including colon cancer and Dravet Syndrome, a severe seizure disorder.

By functioning as a GPR55 “antagonist,” CBD may confer a tumor-suppressing and anti-epileptic effect, although clinical studies have yet to confirm whether this mechanism of action is applicable to humans as well as animals.

At the 2017 ICRS conference, numerous presentations focused on other areas of cannabinoid science that do not involve CBD but are nonetheless relevant for cannabis clinicians and patients. Some highlights: • Chronic cannabis use: Carrie Cutler, assistant professor at Washington State University, provided a much-needed rejoinder to scientifically dubious assertions that chronic cannabis use during adolescence causes brain damage and significant detrimental effects on cognition and IQ. Her study found that after controlling for confounding variables no “significant effects of cannabis use were detected on … measures of memory or executive functioning” other than “modest problems with verbal free recall (i.e., remembering lists of items) and prospective memory (i.e, remembering to do things in the future).” A second study presented by Cutler drew attention to marijuana’s stressMary’s Prime Time • Issue 2 • 2018

Martin A. Lee

cell’s nucleus, thereby reducing the rewarding effects of nicotine and nicotine-dependence in mice. In a separate study of morphine withdrawal, Di Marzo and a team of international researchers concluded: “Oleoyl Glycine is a newly discovered endogenous cannabinoid-like compound that may have therapeutic potential in the treatment of addiction.”

• Pain relief: Temple University scientists found that “cannabinoids used in combination with opioids have the potential to reduce the dose of opioids needed for analgesia.”

Jenny L. Wiley, a scientist with RTI International in North Carolina, and her colleagues at Washington State University reported encouraging results regarding the use of THC as a prophylactic treatment for chemotherapyinduced peripheral neuropathy. “Preliminary data suggest that THC administered chronically during the course of paclitaxel treatment decreases the development of mechanical allodynia [heightened sensitivity to pain] in both male and female rats.”

• Sleep: Gwen Wurm at the University of Miami reported that medical cannabis use is associated with a decrease in the use of prescription and over-the-counter sleep medications. Moreover, according Wurm’s poster, “There is a strong relationship between use of medical cannabis for sleep and for pain.”

ICRS 2017: A Report from

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• The CB2 receptor: Tel Aviv University scientist Bitya Raphael identified an endogenous hormone H4(99103) that activates the cannabinoid CB2 receptor, which regulates immune function, metabolic processes and the peripheral nervous system. This is the first study showing that an endogenous circulating peptide signals via the CB2 receptor. A poster presented by Makenzie Fulmer at East Tennessee State University described how CB2 receptor

dysfunction increases plaque calcification in a mouse model of atherosclerosis.

There were many other significant presentations during the four-day ICRS conference in Montreal that warrant mention – too many to adequately address in this summary. Project CBD looks forward to further developments next year when the ICRS convenes again at Leiden University in the Netherlands.

IACM 2017: A Report from Cologne General Session Reporting by Alice O’Leary Randall The Committee concluded there is conclusive or substantial evidence for effective cannabis or cannabinoid treatment in r. Donald Abrams summarized the recent findings of the treatment of chronic pain, nausea and vomiting associated the U.S. Committee on the Health Effects of Marijuana: with chemotherapy treatments, and improving spasticity An Evidence Review and Research Agenda. The 16-member associated with multiple sclerosis. It gave a rating of “moderate” committee was charged with “conducting a comprehensive evidence for use of cannabis in treating sleep disturbances review of the current evidence regarding the health effects of associated with obstructive sleep apnea syndrome, fibromyalgia, using cannabis and cannabis derived products.” The report was chronic pain, and MS. There is limited evidence for increasing commissioned by the appetite and decreasing Health and Medicine weight loss for HIV/ Division (Formerly the Highlights from IACM Meeting AIDS patients, Institute of Medicine Tourette syndrome, • Cognitive impairment in “old” mice was reversed by ultra-low doses of [IOM]) of the National anxiety, or PTSD. And, delta-9 THC. Given just 0.002 mg/kg of THC the mice performed Academies of Sciences, in a confusing bit of significantly better in a series of standard tests. (See Sarne, page 9) Engineering and jargon, the Committee Medicine. The IOM is stated there was • The Syqe-Exo is a cannabinoid delivery device that resembles an no stranger to reviewing limited evidence that Advair inhaler. The manufacturers presented data that demonstrated cannabis literature cannabis is ineffective ease of use and efficient dosing of cannabis while the the patient was having done so in 1982 for dementia, imhospitalized. (See Eisenberg, page 9) and 1999. So it has to proving intraocular be said that this report, associated • The first large-scale epidemiological studies of cancer patients and aged pressure completed in rather with glaucoma, and populations, both conducted in Israel, demonstrate patient satisfaction record breaking time (it depressive symptoms with medical cannabis as well as demonstrable improvement in first convened in March associated with consymptoms. (See Schleider and Abuhasira, page 8) 2016 and released its ditions such as chronic report less than one pain. year later in January 2017), does not cover any new ground.

It did exhaustively review the literature, retrieving 24,000 The complete report is available in hard copy or Kindle version. abstracts initially but reducing the number actually reviewed The formal title of the report is The Health Effects of Cannabis and to 10,700. From that number it arrived at nearly 100 research Cannabinoids: The Current State of Evidence and Recommendations for Research. A free copy can be downloaded from the National conclusions related to cannabis or cannabinoid use.

Academy website (https://www.nap.edu/catalog/24625/theOf course the Committee called for more research, proposing health-effects-of-cannabis-and-cannabinoids-the-current-state). a “national cannabis research agenda” that is funded by public It is also available in hard copy or Kindle version. agencies, philanthropic and professional associations, private companies, and clinical and public health research groups”.

This is the Committee’s #1 recommendation followed by Evaluating the impact of cannabis use in the human 2) improve research quality, 3) a rather ominous suggestion laboratory and via patient registry surveys to “improve surveillance capacity,” and 4) “address research barriers” which, amazingly, does not address re-scheduling. Ryan Vandry and his colleagues in Maryland, New York, and Instead it calls for creation of another committee that can North Carolina have been looking at administration routes, “fully characterize the impacts of regulatory barriers to cannabis comparing oral, smoked, and vaporized cannabis products. research.” Quite an astonishing bit of side-stepping since it is While it may seem that these issues have been well addressed patently obvious to all that the primary impediment to research in previous NIDA-sanctioned research the group did include vaporization which scored the best in terms peak drug effects is the current scheduling.

Cannabis-based medicines: an introductory overview

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IACM 2017: A Report from

suggesting that vaping may be the more efficient method of cannabis delivery. The researchers also noted that “blood cannabinoids were better biomarkers of acute drug effects than oral fluid cannabinoids.” The team was unable, however, to correlate either marker with performance on cognitive task.

Of more interest to the average cannabis patient was Vandry’s brief discussion of a collaborative project between Johns Hopkins University School of Medicine and the Colorado based Realm of Caring to gather epidemiological data as to how individuals are using cannabis medically. The team has an online survey that participants complete every three months.

At present the database consists of almost 1,000 individuals (500 cannabis users and nearly 400 non cannabis users for a baseline). All are asked about their medical condition and cannabis users are asked about route of administration and strains of cannabis, and outcomes. Unfortunately the full analysis of the study has not been completed but the data does show that cannabis provides benefits in terms of fewer hospitalizations and better quality of life. One interesting preliminary finding is that cannabis seems to additive in terms of the number of drugs that a patient uses. Vandry has not seen a lower use of conventional medications among the medical cannabis users. He was, however, quick to remind the data is preliminary.

In closing, Vandry hit on a subject that would weave in and out of the weekend’s presentations: accurate dosing. With so many cultivars of medical cannabis available (both in terms of the plant chemovars and administration routes) “trying to collect and accurately gauge the information has been a monster.”

Current cannabis-based medicines: a clinician’s perspective Kirsten Müller-Vahl is a neurologist and psychiatrist in Germany where she works at the Hanover Medical School. She advocates a “pragmatic” approach when using conventionally available cannabis-based medicine (CBM) or synthetic cannabinoids such as nabilone. She noted that several CBMs are legally available in Germany including pure THC (dronabinol) and pure CBD:THC at a 1:1 ratio (Sativex). She says that “in most patients, very soon it becomes clear, whether or not CBM are effective and well-tolerated” but it can take time to adjust individual treatment. She advised doctors to pay attention to a patient’s preferred method of administration indeed she stressed it is “important to acknowledge patients’ preferences.”

Müller-Vahl advises the inhalation route whenever possible and advises that sometimes a combination of routes is preferable.

And she made a plea for researching other substances, noncannabinoids, that can also have an effect on the ECS. For example, the tongue twisting substance “palmitoylethanolamide (PEA) enhance(s) the action of [the endogenous cannabinoid] anandamide through an increase in the affinity for receptors and/or a decrease in enzymatic degradation achieving a so called “entourage effect” and enhanc[ing the] beneficial effects of CBMs.” In other words, there are substances out there that can have a dramatic impact upon the ECS that we need to study as much as externally available cannabinoids.

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Epidemiological Characteristics, Safety And Efficacy Of Medical Cannabis In Older Subjects Ran Abuhasira, of Israel’s Tikun Olam, studied the data of 1,946 patients who were aged 65 years or more. They suffered from a variety of ailments including cancer, nonspecific chronic pain, Parkinson’s disease, post-traumatic stress disorder, inflammatory bowel disease and others. The average age was 75.8 years. At the six month follow-up a total of 1,010 patients were evaluated. There had been some deaths (249) and some who stopped the treatment (165). Of the remaining 596 patients, 87.7% reported symptom improvement in their condition. Among the symptoms noted were pain, sleep distrubances, anxiety, weakness and digestive problems.

The Effect Of Cannabis On Crohn’s Disease Patients In yet another study conducted under the auspices of Tikun Olam, Timna Naftali studied the effect of cannabis on Crohn’s disease. This relatively small study (total of 39 patients with 18 receiving cannabis and 21 a placebo) looked at Quality of Life (QOL) scores as well as the Crohn’s disease activity index (CDAI). Improvement in the CDAI among those receiving cannabis was significant (dropping from 279.3 to 118.6 after eight weeks of treatment). The placebo group CDAI also dropped but far less significantly (291.2 to 212). In the QOL scoring there was little movement in the placebo group (71.6 before the study, 79.9 after) whereas the cannabis group showed dramatic improvement (74.8 to 93.6).

These findings are tantalizing for those afflicted with inflammatory bowel disease (IBD) which includes Crohn’s disease. In the U.S. there are 1.6 million patients with IBD.

Medical Cannabis for ADHD: A Medical Sociological Patient Case Study of Cannabinoid Therapeutics in Finland Aleksi Hupli’s case study of an adult ADHD (attention deficit/hyperactivty disorder) patient in Finland highlights an interesting conundrum encountered by cannabis scientists and ADHD patients alike: numerous studies have explored cannabis and ADHD but most studies, according to Hupli, “interpret cannabis use automatically, and often misleadingly, as drug abuse.” Hupli maintains that cannabis is an effective medication for ADHD and cited a recent study from Norway in which ADHD patients who illegally used cannabis reported they did so to treat the symptoms of their ADHD. Hupli concluded that among the biggest obstacles to ADHD patients in Finland who use cannabis is the attitude and knowledge of the attending physician.

Hupli’s presentation was underscored by a poster presentation from Eva Milz of Berlin. She attempted a study of number ADHD patients with cannabis flower obtained via German pharmacies after special permission was obtained. The patients reported an improvement in symptoms but the study was crippled by lack of support and patients having to pay high prices for for the cannabis flower. 

IACM 2017: A Report from

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Cancer and Cannabis Presentations It is widely accepted that cannabis can be a palliative adjunct to cancer chemotherapy: less pain, appetite stimulation, reduction of nausea and vomiting, better sleep and less depression are just a few of the benefits that can be obtained through the use of cannabis. Additionally there is evidence that some cannabinoids have anti-tumor properties. At the IACM meeting there were reports on these aspects of cannabis use as well several case studies presented as poster sessions.

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autophagy” (self destruction of harmful cells). But Velasco also cautions that much is unknown about the interactions of cannabis with other physiologic functions. A naturally occurring growth factor (also called cytokines) called Midkine (MK), for example, interferes with the anticancer ability of cannabis. Thus in individuals who may have higher levels of MK this can lead to a bad prognosis for the GBM patient.

There are dozens of these cytokines as well as other factors that can interact with cannabis thus contributing to an almost individualized tailoring of therapies, a direction that oncology is heading towards as physiology becomes better understood.

ihi Bar-Lev Schleider described a study of more than 2,000 cancer patients registered in the Tikun Olam Clinic Velasco is not alone in his interest in this potential use of during a two year time period. This appears to be the largest cannabis. In February of this year, GW Pharmaceuticals epidemiological study to date of the palliative use of cannabis reported “positive top-line results from an exploratory Phase 2 by cancer patients. Just over half the patients (51.2%) were placebo-controlled clinical study of a proprietary combination diagnosed as Stage IV and the most frequent cancers were breast of tetrahydrocannabinol (THC) and cannabidiol (CBD) in 21 (16.7%), lung (13.6%), pancreatic (8.3%) and colorectal (8.1%). patients with recurrent glioblastoma multiforme, or GBM.” The main symptoms were The GW study is just the latest pain (76%), sleep problems in that company’s study of the (72%), weakness (66%), ability of the cannabis plant Cancer Presentations Highlights nausea (53%) and lack of to encourage autophagy (a appetite (48.8%). During the natural and necessary process • A large study of cancer patients in Israel confirmed study approximately 25% of of cell destruction when the remarkable palliative effects of cannabis for cancer the patients died and another something goes awry). Since patients. 95% of cancer patients reported moderate or 9% left the study for varying 2007 GW Pharmaceuticals significant improvement in their conditions. reasons. At the six month has published 15 studies followup of slightly more than • Studies are showing cannabis in cancer treatment on the topic. (https://www.

800 patients remaining in the is best when used as an additive to conventional gwpharm.com/about-us/ study 95% reported moderate medications. news/gw-pharmaceuticalsor significant improvement in achieves-positive-results• Interaction of cannabis with other physiologic systems their condition. Researchers phase-2-proof-concept-studyis not very well understood and can make tailoring concluded that cannabis as glioma) cannabis for treatments very difficult. a palliative treatment for cancer patients seems to be Poster Sessions • Glioblastoma seems particularly responsive to well tolerated, effective and cannabis treatment. safe option to help patients There were also five poster cope with the malignancy sessions that dealt with • Cannabis oil may be an effective therapy for patients related symptoms. cancer-specific topics. A with malignant melanoma. poster by Dr. Debra Kimless Guillermo Velasco of the underscored some of the Complutense University in positive reporting in Velasco’s Madrid, Spain gave a presentation entitled “Promising Future session. She offered three case studies in which low dose, Directions: Cannabinoid Medicines vs. Cancer.” Spain has whole plant cannabis was used in treating cancers. The cancers been at the forefront of the fascinating research into the anti- included one case of GBM, one anaplastic astrocytoma (a rare tumoral properties of cannabis. Dr. Velasco has been studying brain tumor) and one metastatic ALL (acute lymphoblastic the topic since 2001. leukemia). In each case improvement was noted after use of cannabis oil which contained both acid and decarboxylated At the Cologne meeting, Velasco presented data on the anticannabis. tumoral properties of cannabinoids in treating glioblastoma, an aggressive brain tumor also known as glioblastoma multiforme Another case study came from Frances DeForrest of Montana (GBM). Increasingly it appears that cannabis is best used as and involved the use of cannabis oil to treat a malignant an additive to chemotherapy agents. In GBM, for example, melanoma. In addition to topical application of the oil the Velasco reports cannabis and temozolomide (the primary patient also consumed one capsule daily. Oral ingestion of the GBM chemotherapy agent) “produce a strong anticancer oil became a problem as the patient developed dizziness and effect, which correlates with an intense activation of cytotoxic lethargy. Oral dosing was stopped but topical application (once

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Cancer and Cannabis Presentations

a day) continued and the melanoma resolved.

Another team from Spain provided some promising pre-clinical data on using synthetic cannabinoids to treat AML (acute myeloid leukemia). A German team studied the effects of CBD on the body’s “master regulators” with a goal identifying cellular response and potential biomarkers of the antitumor effect of cannabis. And a team from Israel looked at 13 different chemovars of cannabis with respect to anti-cancer properties and found considerable promise with many variations. Like the case studies of Dr. Kimless noted above, this group determined

“whole Cannabis extracts were found to be more potent at lower concentrations (4 μg/mL) in comparison to using pure Δ9THC (8 μg/mL) to produce the same amount of cell death when applied to specific cancer cell lines.”

The need for aggressive clinical study in this area is obvious.

Additionally it becomes more apparent that the whole plant is superior to synthetics but may require significant tailoring to individual cases until we gain a better grasp of the interaction of the ECS with other physiological systems. 

Reversal of Age-Associated Cognitive Impairments

by Ultra-Low Doses of Tetrahydrocannbinol (THC) Presented by Yosef Sarne, Tel Aviv School of Medicine

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uch a provocative title was certain to catch the eye of conference attendees. It is a given that we all age. And most of us know someone who has suffered from age-related cognitive impairment. A low dose solution of anything that would help us adapt to these natural and often troubling occurrences would be welcome indeed.

Presenter Yosef Sarne of the Tel Aviv University School of Medicine has been exploring the effect of THC on the brain since 2012. He generated significant news in May 2013 when he announced his findings that a micro-dose of THC appeared to protect the brain from injury. Such a finding has obvious implications for literally dozens of possible applications from daily supplements as a neural protectorate to treatment of brain injury from sports, accidents, cerebral events, or war.

After announcement of his findings in 2013, Sarne continued his research and pharmaceutical startup Therapix Biosciences has begun the formal process of moving the drug (in this case the existing synthetic cannabinoid, dronabinol) through the Food and Drug Administration for possible marketing in the U.S. Sarne’s previous study focused on mice and ultra-low doses of THC (0.002 mg/kg) following introduction of a brain “insult” which could be hypoxia, deep anesthesia, MDMA-

toxicity, epileptic seizures or neuroinflammation. Injection of THC either seven days before or seven days after the “insult event” provided the mice with reduced inflammation and improvement in symptoms. Remarkably these positive outcomes were effective for up to seven weeks.

The goal of the study presented at IACM was to determine whether the same ultra low dose of THC would reverse agedependent cognitive decline. The aged mice (18-24 months) were tested with a series of standard cognitive tests and fared significantly worse than young mice (3-4 months) in the same tests. Old mice who were injected once with low-dose THC fared significantly better then their cohorts who were not injected with THC. Indeed they “performed similar to naive young mice in all the tests.”

Sarne further reported that his team discovered the THC injection elevated the amount of SIRTI1 proteins which have been suggested to play a part in the pathology of various neurodegenerative diseases and mediates the effects of melatonin, caloric restriction, and resveratrol (a natural phenol produced in response to injury). The precise import of this discovery remains to be seen but this demonstrates, once again, the remarkable interaction of cannabinoids on the entire physiology of the individual, in this case mice. 

Cannabis Treatment in Hospitalized Patients Using the SYQE-EXO Inhaler: Results of a Pilot Open Label Study Presented by Elon Eisenberg, Technion-Israel Institute of Technology

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linicians around the world are begging for methods that allow accurate dosing of cannabis for their patients. So the presentation by Elon Eisenberg of Syqe (sī/kēē) was highly anticipated and it did not disappoint. The Syqe-Exo Inhaler can go a long way towards helping the physician establish appropriate dosing regimens, even remotely. Beyond that, it can allow patients to continue using inhaled cannabis in Mary’s Prime Time • Issue 2 • 2018

environments that have zero tolerance for smoked or vaped products, e.g. hospitals, nursing homes and even schools.

The Syqe-Exo is a modified version of the Syqe inhaler which, like many inhaler products, allows the user to insert a cartridge with pre-measured doses that can be inhaled as directed. The technology is so clever that some versions allow Reversal of Age-Associated Cognitive Impairments

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remote controlled dosing, in other words the inhaler can be programmed by a signal from the healthcare practitioner. This allows regular dosing but can be over-ridden to allow as needed doses. And if that isn’t enough for you listen to this: “The Syqe Inhaler utilizes selective 100 microgram dosing precision, realtime thermal & flow controllers, lung interfacing and wireless connectivity.”

One more amazing thing: the inhaler uses raw plant material, not oils, allowing the patients to benefit from all aspects of the raw plant.

The study reported in Cologne involved the re-designed SyqeExo, specifically engineered for environments that must avoid the “personal and environmental hazards of smoking.” This was an open label study, meaning there was no attempt to disguise the drug to either the patient or the hospital staff. The study is ongoing and Eisenberg reported on 22 participants thus far. All used either smoked or vaporized cannabis legally

before their admission to the hospital and the study. The device gained high marks for ease of use, perception of inhalation end, and overall satisfaction with the device.

What is particularly appealing about the device is the efficiency of delivery. In the reported study “patients consumed significantly reduced amount of daily Cannabis in comparison to their current home use: 54 mg [32-96] mg vs 1000 mg [6603300] mg per day.”

Barring unforeseen events, it seems fair to predict that Syqe inhalers have a bright future in cannabis therapeutics. For further information: http://www.syqemedical.com.

And Syqe is not the only one looking at inhalation of cannabis powder via inhalers. A Poster session by Andreas Boeckl of Flurry Powders in California. He reported successful production of inhalant ready cannabis dry powders. http:// flurrypowders.com 

Cannabis Chemovars and Genetics Report prepared by Justin Kander Research & Development Coordinator, Aunt Zelda’s

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annabis is a particularly unique plant in the botanical world, and there has been continuous disagreement about how to describe it. Two talks in Cologne addressed the increased understanding of the plant’s history and chemical nature and is leading to a revolution in its classification.

Ultimately this will help everyone work better with the plant.

Dr. Ethan Russo, a foremost authority of cannabis botany and chemistry, shared important facts about cannabis classification and chemistry in his talk "Chemovars (and a Comparison of sativa and indica).”

The cannabis species was first formally described by Carl Linnaeus, the Swedish botanist who pioneered the binomial naming system of organisms. In his seminal 1753 book Species

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Plantarum, Linnaeus classified the cannabis plant as one species – Cannabis sativa. The French biologist Jean-Baptiste Lamarck later described another form of the plant, Cannabis indica; however, there is no current scientific consensus on whether cannabis is one species or several. There may be several species or one species with several subspecies. Thankfully, the taxonomy of cannabis is not crucially relevant to its medical use, which is determined by measurable biochemistry.

From the medical perspective, what really matters about cannabis is the cannabinoid and terpenoid profile. The combination of these chemicals influences medical potential.

THC and CBD are the most prominent cannabinoids, and their ratio essentially controls the psychoactive potential of a Cannabis Chemovars and Genetics

given plant. Dr. Russo discussed a new system for classifying cannabis developed by Dr. Ernest Small in Canada: Type I (high-THC), Type II (mixed THC/CBD), and Type III (CBD-dominant). Dominant terpenoids can be added to the Type, thus quickly identifying the nature of a cannabis plant.

For example, a Type III-myrcene plant would be expected to have no THC-like psychoactivity and be sleepy, whereas a Type I-limonene plant would be very psychoactive and stimulating.

Dr. Russo is particularly passionate about abandoning the term "strain" from cannabis nomenclature. That term applies to bacteria, not plants. He believes the optimal term is chemovar, since the chemical variety of cannabis is most important for medical use. Focusing specifically on the chemical constituents of any individual chemovar is the best way to predict effects, rather than the "sativa-hybrid-indica" terminology which dominates the industry.

Dr. Russo was recently involved in a blinded human trial that illuminated many interesting observations about the roles of THC, CBD, and terpenoids. Not surprisingly, patients who used THC and CBD together had less intoxication and sedation than patients who use THC alone. The THC/ CBD users also had reduced anxiety and increased calmness, alertness, focus, energy, and ability to function. The presence of myrcene appeared to decrease energy and alertness, ocimene produced calming effects, and limonene and pinene increased focus. The combination of limonene, ocimene, and linalool promoted "inspiration". More research will reveal how specific cannabinoid/terpene interactions produce unique effects in humans.

It was encouraging to hear Dr. Russo state that advanced genetic modification techniques or synthetic approaches are not necessary to take full advantage of the possibilities from cannabis. Through selective breeding, growers can create any type of plant they want, it just takes time.

Another presentation titled “Biochemical Genomics of Cannabis Strain Diversity” by Jonathan Page, a plant biologist, described the biochemical pathways by which cannabinoids and terpenes are produced. While much of the deep science is not applicable to medical usage, it is interesting to know how the cannabinoids are made. In fact, Dr. Page pointed out that the cannabis plant uses "very tricky" chemistry to produce cannabinoids, engaging in enzyme reactions never before

seen in plants. Ultimately, two important compounds known as olivetolic acid and geranyl diphosphate combine to form cannabigerolic acid (CBGA), the parent cannabinoid. This is further converted to THCA, CBDA, and CBCA by their respective synthase enzymes. The neutral cannabinoids like THC are not directly produced by the plant and only occur through the decarboxylation of the acidic cannabinoids.

Selective breeding affects levels of various synthase enzymes by changing the DNA of plants across generations. The first growers who initiated the resurgence of high-CBD plants were really developing chemotypes with a DNA sequence that coded for more CBDA synthase than THCA synthase.

With all the progress in genetics, it is now possible to start finding more concrete answers about the potential differences between hemp and medical (“drug-type”) cannabis, as well as indica and sativa. Dr. Page collaborated with Dr. Sean Myles of Dalhousie University to explore this, and found hemp was indeed its own unique group and may have a different origin than drug-type cannabis. To analyze sativa and indica, Dr. Page had to rely on the reported ancestry from growers (% sativa/ indica) compared to the genetic ancestry he analyzed. He found there was a moderate correlation between the two ancestries, but overall there is not enough evidence yet to determine whether the sativa/indica classification is truly correct.

In the future, it will be possible to predict the chemical profiles of cannabis plants by analyzing their DNA. Interestingly, Dr. Page worked with Dr. Tim Hughes at the University of Toronto in 2011 to undertake complete genetic sequences of three types of cannabis.

At the time, cannabis was only the 22nd plant species sequenced and the first ever medicinal plant sequenced.

Such work which contributes to our understanding of cannabis genetics will enable better breeding and targeting of specific chemovars to specific conditions.  Justin Kander

Cannabis Law & Politics Report prepared by Alice O’Leary Randall Editor-in-Chief, Mary’s Prime Time

F

ive speakers presented information on the legal status of cannabis in their respective countries: Canada, France, Germany, Israel and the United States. Globally, it seems, the status of cannabis reform is good with significant progress in each of the countries represented. But the reports also demonstrated the complexities that are involved in extricating the world from more than eighty years of global prohibition.

Dr. Jeffrey Hergenrather, reporting on the U.S.A., made this Mary’s Prime Time • Issue 2 • 2018

point abundantly clear with his presentation. He started with the “bright side” facts: 70% of Americans live in states that allow medical cannabis, 90% of all Americans support legal access to cannabis for medical purposes while 60% support full legalization. But Hergenrather chose to take off the rose-colored glasses and provided some stark figures about U.S. incarceration statistics. The U.S. currently has about 2.4 million individuals behind Cannabis Law & Politics

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bars with half that number jailed for drug offense. Despite approximately a half dozen legislative proposals on the federal level that would reform the general prohibition, Hergenrather was not optimistic about passage but he did note that the U.S. Food and Drug Administration is currently reviewing the scheduling status of cannabidiol (CBD). It is unclear when a decision might be forthcoming but with epidiolex (the G.W. Pharmaceutical drug) rapidly completing its final FDA hurdles it is likely an affirmative action will be taken so the drug can move to market.

The story in Canada is radically different with full legalization scheduled for July 2018. Canada’s nationwide medical cannabis program has operated for over 15 years but the program is, in the words of one writer, “staid” by comparison with the U.S. state programs. There are no legally sanctioned dispensaries.

There are approximately 200,000 patients (a number that is increasing by 5-10% every month, according to session presenter Dr. Mark Ware) and 59 companies that service them.

Patients obtain the substance by courier or mail order. Another 7,500 patients have permission to “grow their own” plants. But the big story is the coming legalization and what impact that will have on medical patients. Will legalization overwhelm the medical program? Dr. Ware expressed concerns about the possibility. He recently served on a government committee that has recommended leaving the medical program exactly as it is … for the time being.

Israel is, without question, the current powerhouse of the medical cannabis movement. Speaker Ilya Reznik rather understatedly noted that conditions in Israel with respect to cannabis are “very friendly.” Per capita, Reznik claims that Israel has the largest number of medical cannabis patients in the world. According to Reznik the Israeli Ministry of Health is becoming more active in the issue and is moving towards certification of pharmacies as dispensing agencies. In tandem the agency is calling for the “medicalization” of cannabis products which will “ensure on the one hand an appropriate indication for patients, access to care and supply of good quality cannabis products, and on the other hand appropriate oversight of a product that is defined as a “dangerous drug.”

The “dangerous drug” statement is a nod to the international treaties that bind Israel (and nearly every other nation) to strictly uphold the provisions of the antiquated U.S. Single Convention on Narcotic Drugs of 1961 and its sister treaty on psychotropic drugs from the early 1970s. This drive to “medicalization” of cannabis will undoubtedly lead to yet another explosion of research & development from the tiny nation in the Middle East. U.S. companies are flocking to Israel and partnering with companies there to conduct Phase 1 & 2

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studies on their products. The American companies can then return home and pursue final Phase 3 studies for the necessary FDA blessing. It is a strategy that seems all the more viable since Israel recently approved the export of cannabis.

Germany enacted a law in the first quarter of 2017 that “legalized” cannabis for medical use. According to presenter Franco Grotenhermen “We have a fantastic law that doesn’t work.” The regulations for the German program are still being promulgated and Grotenhermen does not anticipate having German-produced cannabis until 2019. In the interim the country will need to depend on imports from the Netherlands and Canada. The law does not limit the doctor with respect to indications for which cannabis can be prescribed but in order to participate in the program doctors will be subject to “questioning.” This could have a substantial chilling effect on physician participation. Like many speakers at the conference, Grotenhermen bemoaned the lack of education in medical schools with respect to the endogenous cannabinoid system (ECS).

Sébasien Béguerie of France began his presentation by noting that France was a leading country in herbalist practices until the early 20th Century. Like most nations, France began the process of “forgetting” cannabis in the early 1940s when it abolished the French herbalist diploma and then removed cannabis from the country’s pharmacopeia in 1951. Current patients who require medical cannabis in France have few options. Since 2002 there have been four cases in which patients were prosecuted for cultivation of cannabis. All cases resulted in a guilty finding but with no jail time or fine levied. Sativex, the cannabis-based oral spray developed by G.W. Pharmaceuticals for treatment of multiple sclerosis, was approved in 2013 but the French National Authority for Health has disagreed with respect to the distribution price and, as a result, the drug is not available to patients. Beguerie ended his talk with a plea for education in France that will allow physicians and law enforcement to recognize medical cannabis patients.

Another report on country status was provided by a Poster Session authored by Frédérique Bawin from Belgium, a European country that has taken no steps to provide cannabis to medical patients. Some MS patients have been able to acquire the GW Pharmaceutical drug, Sativex. All other patients are out of luck with respect to legal access. Ms. Bawin is a student at Ghent University and is studying the impact of this prohibition on the patients of Belgium. 

Cannabis Law & Politics