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1.0.0 Introduction
1.1.0 Overview of CMAP™ Guide
(Checklist/Appendix A and Compilation/Appendix B)
1.1.1 This checklist (Appendix A) includes factors to consider from a scientific viewpoint in both prospective research and retrospective evaluation of cannabis research in human subjects. To be used with an ongoing compilation (Appendix B) of published and unpublished research, media reportage, and empirical evidence and anecdotal insights collected from exploratory insights from the cannabis community concerning 1) promising prospective research and 2) critical retrospective analysis using this methodology.
1.1.2 This checklist is designed for use by retrospective study reviewers (scientific reviews, personal reviews, media critiques) and prospective researchers (principal investigators and other researchers). The methodology reflects a new approach to evidence-based cannabis science springing from a heritage of more than 10,000 years of cannabis use by humans to improve health and well being, gain insight, and induce relaxation http://druglibrary.org/schaffer/hemp/history/first12000/1.htm. The goal of this methodology is ultimately to improve the quality of cannabis research in humans.
1.1.3 The checklist’s potential value is twofold. 1) It encourages a systematic approach to cannabis research that is not unduly burdened with political or social bias and 2) it provides contextual information about the modern use and culture of cannabis. This contextual understanding is typically lacking in most conventional cannabis investigations.
1.1.4 The checklist and compilation together comprise the Cannabis Map™ (CMAP), a guide to balanced cannabis research. It reflects methodology using the Cannabis Multi-Analysis Process™ (CMAP) for human subjects research.
1.1.5 We hope to use the results of applying this methodology to analyzing published and unpublished studies as well as media coverage as a means to influence progressive social policy and to educate the public about the role of science in understanding more fully the impact of cannabis on human health and happiness.
1.1.6 Further, comments and analysis on the CMAP Blog(s) of published and unpublished studies, as well media coverage will be screened to ensure that content is of a serious analytical nature, elevating a general understanding of the safety and efficacy of cannabis in a manner taking into account the complexity reflected in the CMAP Guide’s methodology.
1.1.7 Finally, we hope to see suggestions that will expand the list of specific studies that should be critiqued using The CMAP Guide. The CMAP Compilation (Appendix B) is initially an outline of topics and areas of research suggested for evaluation.
1.1.8 Recent in-the-news studies and media coverage may be subjected to retrospective analysis. Those studies that exhibit prohibitionist bias will be singled out for criticism. Calls for retraction may be made for faulty studies published in peer-reviewed journals. Media coverage of studies based on misinformation or bias in interpretation of study results will be met with calls for correction.
1.1.9 Prospective studies using the CMAP Guide are expected to be inspired by a combination of input from the medical, scientific, and cannabis communities as well as the press.
1.1.10 The CMAP Guide will continue to expand as new sections are added from time to time.
1.1.11 NOTICE:
Under U.S. federal law and the laws of many states, use or possession of cannabis and preparations from cannabis are illegal unless under an approved exemption by the Food and Drug Administration.
Information on these pages is educational. Nothing on these pages is intended to support, encourage, or promote the illegal cultivation, possession, use, trade, or commerce of cannabis or the breaking of any law.
In the state of Washington, all use of the CMAP Guide, if with cannabis, must be in strict compliance with Washington state law RCW 69.51A or I-502.
1.1.12 MEDICAL DISCLAIMER:
The CMAP Guide is not intended to diagnose, treat, or cure any medical condition. The Food and Drug Administration has not reviewed any of the statements herein.
Please consult your health professional before starting any new health care program or for any advice regarding diagnosis, cure, and treatment of any disease or disorder.
1.2.0 Instructions for Use of this Guide: Prospective Design and
Retrospective Analysis
1.2.1 These instructions for use of Checklist (Appendix A) and the Compilation (Appendix B-pending) are suggested for those engaged in retrospective critical analysis of studies and prospective cannabis research related to the safety and efficacy of cannabis.
1.2.1.1 The CMAP Checklist (Appendix A) is the “x” axis in this analysis matrix and the CMAP Compilation (Appendix B) is the “y” axis.
1.2.1.2 Check items off in the CMAP Checklist if they are relevant or mark them as “not applicable” as you critique a research study retrospectively or design research prospectively, Not all items in the checklist will be relevant to each critical analysis or research design. Some issues reflected in the Checklist may not be resolvable with current technologies and funding sources.
1.2.1.3 The CMAP checklist and compilation will continually expand with your suggestions on the CMAP Guide Guest Blog.
1.2.1.4 Please also submit written critiques of published and unpublished studies as well as media coverage of cannabis science in the news. Because of the complexities involved, we have not proposed a means to evaluate quantitative data collected using the CMAP Guide at this time.
1.2.1.5 While there is no cost to use the CMAP Guide for scientific critical analysis, research, or media coverage, we ask that you provide the copyright attributes indicated in 6 and 7 below, helping to publicize it’s availability in the cannabis science community and the larger society.
1.2.1.6 Copyright © 2014-2017 by Robert Bornn and Laura Worth. All rights reserved. Photos by Robert Bornn unless otherwise noted. Web site by Laura Worth Web Design
1.2.1.7 CMAP, CannabisMap, and Cannabis Multi-Analysis Process are trademarks of Robert Bornn and Laura Worth.
1.2.1.8 The CMAP™ Guide was designed for sharing widely to promote better cannabis science. If you share this copyrighted material, please be sure to include this language, attributes, and the copyright notice itself.
1.3.0 Examples of the Variable and Paradoxical Effects of Cannabis
1.3.1 Introductory Comments: To paraphrase an old saying, “The dose makes the poison” (Paracelsus, 15th century founder of toxicology) . (Dose, 1.4.1.3.3) Expanding on that, it is also the final cultivar chemistries combined with the “set and setting” (Psychophysiological Effects of Cannabis, 1.3.7) of the end-user that make the effect. The reported high safety and efficacy range of cannabis typically protects against life-threatening overdoses. Nevertheless, increased knowledge of reported untoward side-effects and their antidotes is important.
1.3.1.1 A review of cannabis research in the U.S. has shown that historically most research has been funded by prohibitionist-biased organizations such as the National Institute on Drug Abuse (NIDA) and requires approval of the Drug Enforcement Agency (DEA) for legal release of cannabis for research purposes. The selection process for their research studies cherry-picks research designed for the purpose of showing harm.
1.3.1.2 A more scientific approach to cannabis research would focus on identifying both positive and negative effect(s) of cannabis through optimal combinations of 1) cultivar chemistries, 2) dose, 3) Method of Extraction (MOE), 4) Method of Administration (MOA), 5) Timing of Administration (TOA), 6) individual genetics and physiology, and 7) individual mental set and setting.
1.3.2 Cultivar selection (Cultivar, 1.4.1.3.2), including final plant chemistries after harvest, drying, storage, and extraction (if any); and the role of the individual’s physiology and mental state determines the effect of cannabis. The dosage (Dose, 1.4.1.3.3) also generates both desirable and undesirable side effects and the individual’s set and setting contribute to the effect, along with cannabis experience level. Additional factors such as age, gender, and genetics also influence effect.
1.3.3 Side effects should be weighed in light of a risk-benefit analysis. It should also be noted that many reported side effects may be the result of the paradoxical effects of cannabis or the effects of a specific cultivar or dose. Further, the same effect may be considered positive by one person and negative by another. For example, it has been noted that cannabis consumption typically results in feelings of euphoria, which most experience as pleasurable but some experience as discomfort.
1.3.4 Both beneficial and harmful side effects from cannabis should be noted as well as their likely cause and proposed further clinical investigation of potential solutions. Solutions for side effects may include a combination of accurate labeling, packaging by suggested dose, public education, careful titration of dosing until an individual’s optimal dose is understood, or abstinence by those who are subject to potential harm.
1.3.5 Some Reported Effects of Cannabis (examples listed alphabetically)
1.3.5.1 Addictive behavior and over consumption can be typically remedied with education, awareness, and moderation.
1.3.5.2 Age and Effects: Some side effects are reported to be associated with age.
1.3.5.2.1 Elders. Elders have reported increased vulnerability from various side effects, including balance issues, short-term memory problems, anxiety, and sometimes increased appetite that interferes with appropriate weight maintenance (see Sections 1.3.1 – 1.3.4) . As with other effects of cannabis, education and moderation can be effective in managing risk.
1.3.5.2.2 The Young. In the young, reported “changes” in brain development require further investigation to determine if these changes are detrimental, beneficial, or neutral (Are they associated with certain individuals who are predisposed to those changes genetically or from social or physiological conditioning, such as may occur in children suffering from PTSD related to child abuse.) The identified brain changes may also be associated with individuals who are predisposed to resisting authority or who are predisposed to value curiosity about the world and themselves.
1.3.5.3 Amotivational Syndrome sometimes associated with cannabis use, which may also have a paradoxically positive effect from the “down-regulation” of certain neural activity. For example, amotivational syndrome associated with cannabis may be implicated by some researchers in “career failure.” On the other hand it may help modulate the behavior of “Type A” individuals with “hostile personalities” that are reportedly associated with cardiovascular disease. Adding to this complexity, dose, selection of cultivar, individual genetics, and set and setting may all affect any possible association between cannabis and Amotivational Syndrome (Introductory Comments to Examples of the Variable and Paradoxical Effects of Cannabis, 1.3.1 – 1.3.4). Additionally, certain cannabis cultivars are popularly used to “chill” while others are associated with increased energy, activity and intense creativity.
1.3.5.4 Anxiety and paranoia. Anxiety and paranoia vs. increased sociability and social ease may be impacted by the specific cultivar selected for consumption as well as dose, set and setting (see Sections 1.3.1 – 1.3.4)
1.3.5.5 Appetite. Cannabis is reported to be helpful for conditions like wasting syndrome, anorexia, and loss of appetite in connection with chemotherapy. Paradoxically, in situations where increased food consumption is not appropriate, the “munchies” associated with cannabis is reported as an undesirable effect that is managed with education and moderation.
1.3.5.6 Asthma. Bronchodilation from certain cannabinoids may be responsible for the reported use of smoked or vaped cannabis (see Method of Administration, Sections 2.7.3.6.1.1 and 2.7.3.6.1.2) to stop acute asthma attacks quickly (see Section 1.3.5.18).
1.3.5.7 Blood pressure decrease is typically a good effect; but when blood pressure is too low it can be accompanied by nausea, light headedness or head spinning/dizziness — possibly leading to dangerous falls or accidents. Cultivar selection and dose are again important (see Section 1.3.5.13.)
1.3.5.8 Circadian Rhythm. Consumption at particular times during the body’s daily circadian rhythm may affect its effectiveness. For example, if the body is naturally ready to produce higher, nighttime levels of melatonin in connection with sleep, cannabis may increase that production. Likewise, cannabis enhances the natural circadian effect of lowered core temperature, which may help promote onset and maintenance of sleep (see Sleep, 1.3.5.19).
1.3.5.9 Digestion. Whether ingested cannabis is consumed on an empty or full stomach may affect research results (see Nausea, vomiting, diarrhea, 1.3.5.16).
1.3.5.10 Euphoria. Euphoria, relaxation and increased sociability, reduction of ADHD (attention deficit hyperactivity disorder), OCD (obsessive compulsive disorder), PTSD (post traumatic stress disorder) vs. amotivational syndrome, paranoia, or inappropriate social behaviors. For example, euphoria associated with certain cultivars may be undesirable in situations where clear assessment of danger is required. On the other hand a low level of euphoria from cannabis may safely counteract the chronic dread associated with clinical depression, allowing a higher level of functionality and well being. (Side effects, 1.3.3 and 1.3.4)
1.3.5.11 Gender and Effects: Some effects are reported to be associated with gender
1.3.5.11.1 Some limited research has indicated that women may have a lower tolerance for THC than men, which would skew research results toward higher side effects from overdosing unless this variable is controlled. If this research is replicated in additional supporting research, this may lead to higher dosing recommendations for men (where THC is concerned). Further research would also be required for clear recommendations that any untoward THC effects might be moderated by terpene or other cannabinoid consumption for women. “Females more sensitive to cannabis; males get munchies,” WSU News https://news.wsu.edu/2014/09/03/females-more-sensitive-to-cannabis-males-get-munchies/#.VBiEZ_ldVU .
1.3.5.11.2 Estrogen production: There is some research indicating that cannabis may affect women’s estrogen production and may therefore be related to issues of infertility. (Introduction to Granny Storm Crow’s List, 2014.)
1.3.5.12 Hyperemesis. Cannabis-induced hyperemesis is a particular condition that is increasingly reported. In this condition nausea and vomiting are protracted, requiring treatment for their cessation (Nausea, vomiting, diarrhea, 1.3.5.16).
1.3.5.13 Heart rate increase that may be associated with anxiety, palpitations, angina. A decrease in dose may reduce an elevated heart rate. Varied cultivars and dosage will have different affects on the heart. (Blood Pressure Decrease, 1.3.5.7).
1.3.5.14 Hyposalivation (dry mouth, with potential for dental issues from inadequate salivation). Use of lozenges may reduce this side effect.
1.3.5.15 Memory. Cannabis has often been reported to negatively affect short term memory (also see effects section on Sleep). Conversely, it has also been identified as a possible therapy for preventing Alzheimer’s syndrome by helping to clear beta-amyloid (plaque) from the brain.
1.3.5.16 Nausea, vomiting, diarrhea. Cannabis has been widely noted as a remedy for nausea and vomiting associated with chemotherapy. It can affect gut motility with varied results. Conversely, it is also sometimes associated with nausea, vomiting, and diarrhea, especially in the naive user or with unintentional overdose. This is typically reversed by adjusting the dose and gaining control of the physiological perceptions of the subjective experience of cannabis sensations. Overdose may lead to dehydration, which may require fluid and electrolyte replacement, especially in children, elders, or the medically frail. (Digestion, 1.3.5.9 and Hyperemesis, 1.3.5.12)
1.3.5.17 Paradoxical Effects from Cannabis. Cannabis is known to cause “paradoxical effects” whereby it may cause diametrically different effects. For example, it may cause anxiety or be an anti-anxiolytic agent; it may often be used to prevent seizures or, more rarely, be implicated in causing seizures. Paradoxical effect is likely to be the result of the interplay of cultivar selection, dose, and the individual’s genetics, psychological set, and physical and social setting (Introductory Comments to Examples of the Variable and Paradoxical Effects of Cannabis, 1.3.1 – 1.3.4).
1.3.5.18 Respiratory. Method of administration may be associated with untoward side effects (e.g., smoking cannabis may be the cause of respiratory side effects and the solution may be vaping, spray, tincture, topical, or edible consumption). Conversely, some lung function increase is reported from the practice of deep inhalation. Successful use of cannabis as an intervention for asthma attack is also reported (Asthma, 1.3.5.6).
1.3.5.19 Sleep. Change in sleep patterns may decrease REM stage sleep, but paradoxically increase slow wave (restorative) sleep. Delayed or less REM may result in reduced memory efficiencies; yet this risk may be off-set by managing insomnia with cannabis, thereby increasing the restorative stages of sleep. Adequate restorative sleep is required for other health benefits, including it’s long-term association with clearing toxins from the brain, thereby possibly reducing dementia risk.
1.3.5.19.1 Cannabis is often reported to help manage insomnia. The cultivar and dose selection is important. (Circadian Rhythm, 1.3.5.8)
1.3.5.19.2 Cannabis may induce sleep by triggering natural melatonin production. If this is the case, established melatonin production during the 24-hour circadian cycle may be disrupted. This may be similar to the body’s reaction to melatonin supplements sometimes taken for insomnia. If this occurs, an adjustment period may be required to return to normal triggering of the body’s production of melatonin. For example, in a study of cannabis use for insomnia management, where the control group is created by using the same subject with manipulation of other variables, it would be important to adjust for this period of potential renewed sleeplessness while the body returns to its natural level of melatonin production.
1.3.5.19.3 Cannabis may affect sleep stages. For example, REM sleep (commonly associated with dreaming) may be delayed or diminished. Conversely, it may increase slow wave sleep (associated with brain and body repair).
1.3.5.19.4 It is reported that sleep disturbances often occur for several nights when frequent cannabis use is discontinued. For example, in this situation subjects may experience temporary excessive REM sleep, known as REM rebound.
1.3.5.19.5 More knowledge of specific cultivars’ influence on sleep will be important in assessing the role of cannabis in safely managing medical conditions and enhancing general health and well being.
1.3.5.20 Social harms. Studies that conclude that social harms (e.g., lives ruined) are caused by cannabis frequently confuse causation with the association of cannabis with it’s federally illegal status. Similarly, social harms may be associated with any social stigma associated with cannabis use or prosecution.
1.3.6 Cultivation, Genetics, and Hybridization.
Modern challenges to popular notions of Indica vs. Sativa landraces and hybridization in light of contemporary growing and harvest practices
1.3.6.1 Landraces
1.3.6.1.1 Though most people are familiar with “Sativa” and “Indica” as the two “main” segregates for Cannabis, there are actually four prominent Cannabis segregates that we can tell apart on a morphological basis. From McPartland/Clarke/Watson (“Hemp Diseases and Pests” 2000) – Cannabis taxonomy morphological key adapted from work by Schultes et al. (1974), Emboden (1974), Small & Cronquist (1976), Clarke (1987), and McPartland/Clarke/Watson (2002):
1.3.6.1.1.1 “1. Cannabis sativa (=C. sativa var. sativa): Plants tall (up to 6 m), stems smooth and hollow, laxly branched with long internodes; petioles short, usually 5-9 leaflets per leaf, leaflets lanceolate, largest leafleats average 136 mm long (length / width ratio = 7.5); racemes have long internodes, and achenes are partially exposed; achenes (seeds) usually >3.7 mm long, somewhat lens-shaped with a blunt base, surface dull light-to-green and usually unmarbled, seeds usually adherent to plants at maturity. Cultivated for fibre, oil, and sometimes drugs.”
1.3.6.1.1.2 “2. Cannabis indica (=C. sativa var. indica): Plants shorter (under 3 m), stems smooth and nearly solid, densely branched with shorter internodes; petioles shorter, usually 7-11 leaflets per leaf; leaflets narrow lanceolate, largest leaflets averging 92 mm long (l/w ratio = 10); achenes average 3.7 mm long, less lens-shaped, with more rounded base, surface green-brown and marlbled or unmarbled, with or without an abscission layer. Cultivated primarily for drugs but also used for fibre and oil.”
1.3.6.1.1.3 “3. Cannabis ruderalis (=C. sativa var. spontanea): Plants small (usually under 0.5 m), stems smooth and hollow, occasionally unbranched; petioles short, usually 5-7 leaflets per leaf, leaflets elliptic, largest leaflets average 60 mm long (l/w ratio = 6); achenes small with a pronounced abscission structure at the base, surface dull green and marbled, abscission layer fleshy with oil-producing cells, seeds readily shed from plant. Not cultivated.“
1.3.6.1.1.4 “4. Cannabis afghanica (=C. sativa var. afghanica): Plants short (under 1.5 m), stems ribbed and nearly solid, densely branched with short internodes; petioles long, usually 7-11 leaflets per leaf, leaflets dark green and broadly oblanceolate, largest leaflets averaging 130 mm (l/w ratio = 5); racemes have short internodes, and achenes are not exposed; nested, compound bracts sometimes produced; achenes usually <3.0 mm long, nearlt round with blunt base, surface shiny grey and marbled. Cultivated exclusively for drugs, primarily hashish.”
1.3.6.1.1.5 “McPartland/Clarke/Watson (2002) opine that researchers frequently misname these Cannabis segregates. C. indica is frequently misnamed C. sativa, and C. afghanica is frequently misnamed C. indica. Clarke (1987) attempted to correct the confusion by elevating C. afganica Vavilov from its original subspecies level (=C. sativa f. afghanica Vavilov 1926). Clarke noted that Schultes et al. (1974) lumped C. afghanica with C. indica. Unfortunately, Cannabis from Afghanistan has come to typify C. indica, especially in the eyes of marijuana breeders. This is incorrect; Lamarck (the botanist who named C. indica) was entirely unfamiliar with Afghan Cannabis. His taxon refers to the biotype from India (indica). Marijuana breeders’ use of the name ‘indica’ for afghanica biotype has become entrenched, causing extensive confusion. Some breeders (e.g., Schoenmakers 1986) double the confusion by calling afghanica plants ‘ruderalis species’.”
1.3.6.1.1.6 In summary: C. sativa var. sativa is what most people name as “Hemp”; C. sativa var. indica is what most people mistakenly name as “Sativa”; C. sativa var. afghanica is what most people mistakenly name as “Indica”.
1.3.6.2 Hybridization
1.3.6.2.1 After 40 years of breeding, the marijuana plant has been substantially changed. Breeders began with landraces then widened the selection. Most modern varieties are many hybridizations away from the original landraces. They have been domesticated to produce more higher quality flowers in less time.
1.3.6.3 Growing and Harvest Time, Plant Maturation, and 24- Hour Fluctuation
1.3.6.3.1 The role of contemporary growing and harvest practices in each plant’s development of bioactive phytochemicals affects the character of each plant. Cannabis science may reveal that these exogenetic factors are more significant in safety and efficacy issues than the genetics of each plant.
“Terroir” is a term used to describe a factor known in the beer industry (hops) and in wine making (grape clones). http://en.wikipedia.org/wiki/Terroir. Environment and epigenetics can combine to make hops from a particular area unique. All plant species have methylated DNA, which causes some genes to be “switched on” more easily than others. Differences in soil, day length, temperatures, amount of rainfall and terrain all may influence the methylation process. per John Henning, hops geneticist for the U.S. Department of Agriculture in Oregon: http://draftmag.com/features/the-dirt-on-terroir.
1.3.6.3.1.1 Harvest Time
1.3.6.3.1.1.1 From Ed Rosenthal (“Marijuana Grower’s Handbook” 2010):
1.3.6.3.1.1.1.1 “The intensity of sunlight declines from the equator to higher latitudes because the sun hits the equator at a direct perpendicular angle. As the latitude increases the sun’s angle becomes more oblique. Landraces from equatorial areas have adapted genetically to the intense sun. To grow well, they need more intense light than most indoor plants receive. Equatorial plants (“Sativa” [actually C. sativa var. indica]) are fast growing and have large stem spaces (internodes) between leaves. They are not the tight hybrids that gardeners are accustomed to, but their wilder cousins must gain height and canopy space quickly to survive. Indicas [actually C. sativia var. afghanica], on the other hand, adapted to a far less habitable environment. They just had to tough out uncertain weather and drought, short summers and poor soil. A compact thick-leaved plant is better equipped for the windy Himalayan foothills than a tall lanky one.”
1.3.6.3.1.1.1.2 “Time waits for no one, but you must wait for sativas [actually C. sativa var. indica]. They often ripen in November, December or January outdoors. Indoors they have a 10 to 16 week ripening time.”
1.3.6.3.1.1.2 Indicas [actually C. sativa var. afghanica] usually ripen within 8 to 10 weeks. Ruderalis are a wild or feral variety of auto-flowering marijuana. A few weeks after germination, the ruderalis plants begin to produce flowers while continuing to grow.
1.3.6.3.1.2 Fully Mature
1.3.6.3.1.2.1 Quality control extends to include flowering times. Commercial growers harvest flowers early in order to get more harvests per year. By pulling their plants early commercial growers never let their plants grow to full potential. All flowers have a specific “Harvest Window.” This window refers to a period of time that the flower is “ripe” and at its peak potential. The standard harvest window is around 2-3 weeks. During the harvest window flowers mature until, at a certain point, they start to degrade. The outcome depends on crucial decisions, made by the grower, about when the plant is picked.
1.3.6.3.1.3 24-Hour Cannabinoid and Terpene Fluctuation
1.3.6.3.1.3.1 Choosing what time of day to harvest during the circadian rhythm of cannabinoid and terpene synthesis also plays a pivotal role in optimization of peak potency of the plant.
1.3.6.3.1.3.2 From Ed Rosenthal (“Marijuana Grower’s Handbook” 2010):
1.3.6.3.1.3.2.1 “As it matures sexually, marijuana produces [cannabinoids and] terpenes in the glands (trichomes) that surround the flowers. [Cannabinoid and] Terpene levels increase during the dark period and reach their peak just before dawn. During the day they evaporate and fill the surrounding air with odor to warn predators. By the end of the day, at dusk terpene (and cannabinoid) levels are at their lowest.”
1.3.7 Psychophysiological Effects of Cannabis (set and setting)
1.3.7.1 Set and Setting are considered especially significant in cannabis research due to diverse psychoactive effects that may be present in various degrees depending on the specific cultivar and other factors, including the “set and setting” as described below.
1.3.7.2 Examples of psychoactive effects attributed to specific cultivars may include diverse and paradoxical characterizations of the “high” (for example, as an anti-depressant, stimulant, relaxant, anti-anxiolytic, euphoric, intoxicant, hallucinogen, or psychedelic).
1.3.7.3 The affect on the set and setting of these factors needs to be reflected in research conclusions. At some point the set is so affected by the research, that it may not be realistic to claim causation.
1.3.7.3.1 Set
1.3.7.3.1.1 Set refers to the subject’s internal landscape. Examples of factors comprising a subject’s “set” include mental state, expectation effect, prior level of experience with cannabis (whether a naive or experienced user) and a subject’s personality as it affects the personalized experience with cannabis.
1.3.7.3.1.2 Strategies for addressing these variables include design of a blind study with respect to cultivar/strain. Method of administration might also be double blind; for example edibles, lotion, tincture, or spray could be infused with cannabis or not. This strategy might minimize the subject’s expectations and the role of the subject’s naivity or prior experience with cannabis.
1.3.7.3.1.3 Similarly regarding set, personality testing before, during and after administration of cannabis may be helpful in determining whether cannabis causes personality changes and in what direction (toward or away from pathology).
1.3.7.3.2 Setting
1.3.7.3.2.1 Setting refers to the physical and social environment as well as other factors in the subject’s external landscape. A study’s design must reflect an understanding of how setting may affect the cannabis experience and minimize it as a variable affecting the outcome of the research. For example, the design of a study may focus on the difference between a social setting for vaping with friends vs. vaping with strangers.
1.3.7.4 Physiological tests of subject
1.3.7.4.1 For example, serum analysis for melatonin at appropriate intervals may be a significant factor in determining whether to commence a new cultivar (in the same patient as a control) for testing of the cultivar’s effectiveness on insomnia.
1.3.7.4.2 Serum analysis for relevant bioactive cannabis molecules (metabolite) may be desirable.
1.3.7.4.3 Mental states such as anxiety may be measured with self-reporting scales or measured more objectively with serum metabolites, heart rate, galvanic skin response, and stress hormone levels.
1.3.8 Other factors unique to cannabis research
1.3.8.1 Controlling for multiple methods of administration
1.3.8.1.1 Is the method of administration studied appropriate to the interpretation of results.
1.3.8.1.2 For example, a study’s rejection of topical lotion or vaped flowers for rheumatoid arthritis because smoked cannabis may be correlated with respiratory pathology (McGill University 2014.)
1.3.8.2 Complexity of set and setting can lead to misinterpretation of results
1.3.8.2.1 Subject bias: prohibition or cannabis community’s strong influence on expectations of subject
1.3.8.2.1.1 influence on set and setting
1.3.8.2.1.2 placebo effect
1.3.8.2.1.3 expectation effect
1.3.8.3 Researcher bias: prohibition or cannabis community’s strong influence on expectations of researcher
1.3.8.3.1 influence on set and setting
1.3.8.3.2 placebo effect
1.3.8.3.3 expectation effect
1.3.8.4 Subject selection criteria
1.3.8.4.1 Exclusionary criteria – age, gender, ethnicity and other demographics are often excluded from studies, leading to data and results that can not be generalized to a wider population.
1.3.8.4.1.1 Depending on the research design, such exclusionary criteria may be appropriate or not. For example, excluding subjects with a history of opiate use for pain in a study of cannabis use for pain could exclude the very individuals most likely to be helped by cannabis. On the other hand, it could be appropriate to exclude an opiate user as a subject in a study investigating whether there is a positive effect from cannabis on sleep apnea.
1.3.8.4.2 Self-selected volunteers may create bias
1.3.8.5 Cannabis sample selection criteria
1.3.8.5.1 random
1.3.8.5.2 not random
1.3.8.5.3 Complexity of entourage issues – whole plant vs. selected cannabinoids (evaluate entourage issues)
1.3.8.5.4 Cultivar rotation
1.3.8.5.4.1 Cannabis is noteworthy for a “new cultivar effect,” whereby effectiveness may wear off until a new cultivar is used by the subject. If there is potential for “new cultivar effect” the study design may include a change or rotation of the cultivar.
1.3.8.5.5 Continued use of a cultivar
1.3.8.6 Importance of sensitivity and specificity of cultivar and anticipated effect match-up
1.4.0 Glossary and Other Resources
1.4.1 Glossary of Terms
1.4.1.1 Note: This Glossary of Terms is expanding, including sources and acknowledgements.
1.4.1.2 Nine examples of potential glossary terms:
1.4.1.3.1 Characterization
1.4.1.3.1.1 Characterization of cultivars is typically from a combination of annecdotal crowdsourcing from the recreational and medical cannabis community and data gathering at various levels of reliability depending on the scientific method and source. For the most part, popular characterization of a cultivar cannot be assumed to be reliable because of such research variables as expectation effect, new strain effect, experience level of subject, and self-reporting by subjects. Such characterizations may be considered similarly to anecdotal and exploratory research, requiring verification
1.4.1.3.1.2 For example, “Super Lemon Haze” is characterized by Medical Jane as a hybrid of the land races, sativa and indica. Its descriptors include sweet, cool aroma, with slight lemon undertones, uplifting, energetic, invigorating. Medical Jane’s assessment of its possible uses is that it may help fatigue, depression, bipolar, and PTSD. http://www.medicaljane.com/review/super-lemon-haze-an-energizing-strain/#
1.4.1.3.2 Cultivar
1.4.1.3.2.1 The term “cultivar” as used in the CMAP Guide refers to the specific plant chemistry that is the result of a combination of plant genetics, growing techniques, harvest, drying, storage, and extraction (if any) processes. (Also see Strain, Section 1.4.1.3.6)
1.4.1.3.3 Dose
1.4.1.3.3.1 A dose of cannabis is the quantity administered by self or others, applied, or eaten. Tolerance to a dose may vary across individuals or change with experience over time, reflecting whether a person is an experienced cannabis user; it may vary reflecting an individual’s unique physiology. Overdose may refer to a dose that exceeds an optimal quantity. Equivalence across methods of administration may similarly vary. For example, a typical dose of cannabis that is smoked or vaped may be 10 mg of THC or (pro rata) among other cannabinoids; sublingually 2 mg; or 10-40 mg as an edible cannabis product.
1.4.1.3.4 Genetic Expression
1.4.1.3.4.1 Genetic expression as a result of growing technique is important in classification, leading to an emphasis on phenotype and the percentage of terpenes and cannabinoids in each plant.
1.4.1.3.5 Hybrids
1.4.1.3.5.1 Hybrids are bread into thousands of cultivars (strains) from variations grown from these 3 sub-species: sativa, indica, and ruderalis. Ruderalis has been said to be like a weed, a strain without much practical use, that still occurs in nature. Historically, popular culture has held that sativa strains create “cerebral” highs and indica strains create “body” highs. Frequently medical cannabis dispensaries continue to classify hybrids according to whether they are sativa- or indica-dominant. (Hybridization, 1.3.6.2).
1.4.1.3.6 Institutional Review Board (IRB)
1.4.1.3.6.1 Per wikipedia: “An institutional review board (IRB), also known as an independent ethics committee or ethical review board, is a committee that has been formally designated to approve, monitor, and review biomedical and behavioral research involving humans. They often conduct some form of risk-benefit analysis in an attempt to determine whether or not research should be done. The number one priority of IRBs is to protect human subjects from physical or psychological harm. In the United States, the Food and Drug Administration (FDA) and Department of Health and Human Services (specifically Office for Human Research Protections) regulations have empowered IRBs to approve, require modifications in planned research prior to approval, or disapprove research. IRBs are responsible for critical oversight functions for research conducted on human subjects that are “scientific,” “ethical,” and “regulatory.” http://en.wikipedia.org/wiki/Institutional_review_board
1.4.1.3.6.2 Note that an IRB is charged with the role of protecting subjects from harm, not with assessing the validity of research design. Approval of a study weighs the benefits gained from doing research against potential harm to a subject.
1.4.1.3.6.3 IRB approval is required for studies directly or indirectly funded by Department of Health and Human Services (HHS), creating potential bias in study design resulting from undue influence of prohibitionist federal policy on IRB refusal to approve a study depending on its hypothesis and purpose.
1.4.1.3.6.4 An IRB can be controlled by a university or company engaged in independent research. Alternatively, IRBs can be run independently from the organization conducting research or commercially run . Examples include:
1.4.1.3.6.4.1 “Human Subjects in Medical Research – Stanford University” (controlled by academic or other organization conducting the research; note that organizations can name their IRB whatever they wish).
1.4.1.3.6.4.2 “E&I Ethical and Independent Review Services “is accredited and “performs a full range of clinical research, device research and social, behavioral and educational human subjects research.” per their page on LinkedIn. (controlled by an independent commercial organization in the business of providing IRB services.)
1.4.1.3.7 Strain.
1.4.1.3.7.1 The term “strain” refers to the specific plant genetics that are the result of breeding (if any). (Cultivar, 1.4.1.2.3.2)
1.4.1.3.8 Examples of major cannabinoids
Exogenous cannabinoids are produced by the cannabis plant and possibly other plants. A number of them have also been synthesized. There are more than 200 cannabinoids identified in the cannabis plant, produced in varying amounts depending on genetics, breeding, cultivation, and harvest practices. Cannabinoids and endocannabinoids act on cannabinoid receptors on cells (CB-1 and CB-2) in the animal and human body, constituting the endocannabinoid system (ECS). (http://en.wikipedia.org/wiki/Cannabinoid)
The following are some of the major cannabinoids that are tested for by analytical laboratories with some reported effects cited.
CBG-A (Cannabigerol-acid): the primary, most basic cannabinoid from which all other cannabinoids are synthesized by the plant (e.g., THC-A and CBD-A).
CBG (Cannabigerol – after decarboxylation): relieves interocculuar pressure associated with glaucoma and treats inflammatory bowel disease.
THC-A (tetrahydrocannabinol-acid): anti-inflammatory, neuroprotective, anti-proliferative, anti-spasmodic
THC (tetrahydrocannabinol, THC, Δ9 , Delta-9 – after decarboxylation): a major cannabinoid and the primary psychoactive molecule; euphoric, analgesic, anti-inflammatory, antioxidant, antiemetic
THC 11 (tetrahydrocannabinol – 11): a serum metabolite
THCV (Tetrahydrocannabivarin): modulates immune system through CB2 receptors.
CBD-A (Cannabidiol-acid)
CBD (Cannabidiol – after decarboxylation): anxiolytic, analgesic, antipsychotic, anti-inflammatory, antioxidant, antispasmodic through CB1, CB2, vanilloid, and adenosine receptors.
CBC-A (Cannabichromene-acid):
CBC (Cannabichromene – after decarboxylation): may inhibit cancer cell growth with antiproliferative effects, inhibits inflammation and pain; stimulates bone growth.
CBN-A (Cannabinol-acid)
CBN (Cannabinol): sedative; antibiotic, analgesic, reduces intraocular pressure in the eye (primarily found as a result of THC breakdown during storage and is not very psychoactive, not from CBN-A oxidation).
1.4.1.3.9 Terpenes and their chemically modified cousins, terpenoids are best known as the phytochemicals responsible for the scent of plants. There are more than 100 terpenes with a range of psychophysiologic effects that go beyond scent – many well studied in other plants. Terpenes acting in concert with cannabinoids, flavonoids, and vanilloids are also a major driver of the “entourage effect” in cannabis.
Many terpenes cross the blood-brain barrier. In addition, it should be noted that although olfactory receptors were first discovered in the nose in the 1990s, meriting a Nobel Prize, since then olfactory receptors have also been identified in cells throughout the body. (Stone, A., “Smell Turns Up in Unexpected Places” New York Times, D3, 10/14/14: http://www.nytimes.com/2014/10/14/science/smell-turns-up-in-unexpected-places.html?_r=0).
The following list includes some of the major terpenes, other plants in which they are found, and some of their reported effects. Most professional cannabis testing laboratories can test for the presence of terpenes in cannabis plants and extractions.
1.4.1.3.9.1 Monoterpenoids (highly volatile and likely to be lost or diminished during drying and early storage)
Borneol (camphor, rosemary, and mint) – anesthetic, anti-inflammatory, analgesic
Cineole (eucalyptus) – analgesic for topical uses, stimulant
cis-Ocimene (variety of plants and fruit) – used in perfumery
Limonene (citrus) – energizing anti-depressant, anxiolytic, reduces acid reflux
d-Limonene (orange peel) – hypothermogenic
Linalool (lavender) – relaxant, anesthetic, anti-convulsant, analgesic, anxiolytic, burn therapeutic agent, anti-depressant (via seratonin-receptor transmission amplification)
Myrcene (hops) – sedative for sleepiness, analgesic, muscle relaxant
a-Pinene (pine) – bronchodilator, memory retention aid, anti-bacterial, anti-inflammatory; crosses the blood-brain barrier easily.
Pulegone (rosemary) – may prevent short-term memory loss (acetylcholinesterase protein inhibitor)
Terpinolene (cumin, lilac, apple, tea-tree and conifers) – antiseptic, anti-bacterial, anti-fungal, preservative, treats insomnia in a blend of lilac and lavender.
Terpineol (lilac, apple blossoms): used in perfumes, cosmetics, and flavorings.
1.4.1.3.9.2 Sesquiterpenoids (less volatile)
a-Caryophyllene or Humulene (hops, pine) – anti-inflammatory
b-Caryophyllene (black pepper) – anti-inflammatory, analgesic, protects cells lining the digestive tract, binds to CB2 receptors.
Caryophyllene oxide (oxidated Caryophyllene) – anti-fungal, anti-bacterial
b-Eudesmol (Chinese herb) – anti-convulsive
trans-Nerolidol (ginger, jasmine, lavender, tea tree, lemon grass) – flavoring, perfumery, and may enhance skin penetration for transdermal delivery of therapeutic drugs.
1.4.1.3.9.3 Other Cannabis Terpenes (comments are welcome by “Reply” below)
1.4.2 Sources, Notes, and Acknowledgements
1.4.2.1 Sources
We suggest the following documents and sources, used in creating this CMAP Check List. We are confident that others will help the CMAP Guide advance as a public resource through comments and suggestions from advisors and sponsors. We envision that the CMAP Guide will encourage a high level of editor-moderated commentary with sophisticated vetting, verification, and sharing. Please visit the CMAP Guide or contact us with your input to this process.
1.4.2.1.1 1. Rosenthal, Ed, Ed Rosenthal’s Marijuana Grower’s Handbook, Ask Ed® Edition, Your Complete Guide for Medical and Personal Marijuana Cultivation, Quick American Publishing, Oakland, California, 2010.
1.4.2.1.2 2. Washington State Liquor Control Board (to become WS Liquor and Cannabis Control Board), WAC 314-55-103 “Good Laboratory Practice Checklist.” (for certification of I-502 products), PDF, pp 7-9. (http://www.liq.wa.gov/publications/Marijuana/I-502/Good_Laboratory_Practice_Certification_Checklist.pdf).
1.4.2.1.3 3. American Herbal Pharmacopaeia (AHP), “Standards of Identity, Analysis, and Quality Control”, 2013, http://www.herbal-ahp.org.
1.4.2.1.4 4. The authors’ insights from a critical analysis of numerous published, peer-reviewed studies and recent media coverage re the safety and efficacy of cannabis use.
1.4.2.1.5 5. Insights contributed by our advisory team.
1.4.2.1.6 6. Inspiration and insights from Granny Storm Crow’s List for July 2013, a compilation of positive annecdotal and peer-reviewed studies showing both safety and efficacy for cannabis use. http://www.michiganmedicalmarijuanaclub.org/general-news-a-info/57-granny-storm-crows-list-for-july-2013
1.4.2.1.7 7. J.M. McPartland, R.C. Clarke, D.P. Watson, “Hemp Diseases And Pests: Management and Biological Control”, CAB International, pp 3-4, 2000
1.4.2.1.8 8. R.E. Schultes, W.M. Klein, T. Plowman, T.E. Lockwood, “Cannabis: an example of taxonomic neglect.”, Bot. Mus. Leaflet 23:337-367, Harvard University Press, 1974
1.4.2.1.9 9. E. Small, A. Cronquist, “A Practical and Natural Taxonomy for Cannabis”, Taxon 25:405-435, 1976
1.4.2.1.10 10. R.C. Clarke, “Cannabis Evolution”, MS Thesis, Indiana University, pp 233
1.4.2.1.11 11. Schaffer Library of Drug Policy/Historical References, Ernest L. Abel, “Marijuana, the First 12,000 Years,” 1980. http://druglibrary.org/schaffer/hemp/history/first12000/1.htm.
1.4.2.1.12 12. John M. McPartland and Ethan B. Russo, “Cannabis and Cannabis Extracts: Greater Than the Sum of Their Parts?” Journal of Cannabis Therapeutics, The Haworth Press, Inc., 2001. http://www.cannabis-med.org/data/pdf/2001-03-04-7.pdf
1.4.2.1.13 13. Julie Holland, Pot Book. (general overview of the plant)
1.4.2.1.14 14. Martin Lee, Smoke Signals. (history)
1.4.2.1.15 15. Ed Rosenthal, Marijuana Grower’s Handbook. (growing)
1.4.2.1.16 16. Cannabis Evolution and Ethnobotany (botany & cannabis use throughout history)
1.4.2.1.17 17. Joan Bello, The Benefits of Marijuana. (spiritual use)
1.4.2.1.18 18. Bonnie & Whitebread, Marijuana Conviction. (history of law)
1.4.2.1.19 19. Michelle Alexander, The New Jim Crow. (racism of law).
1.4.2.1.20 20. Dan Baum, Smoke and Mirrors (history of drug war)
1.4.2.1.21 21. Marijuana Legalization (policy of cannabis legalization).
1.4.2.1.22 22. The International Association for Cannabinoid Medicines, http://www.cannabis-med.org/english/bulletin/iacm.php (primary research newsletter and Website).
1.4.2.1.23 23. Wikipedia references are offered as a starting point for basic information on selected topics. Submissions for additional references are welcome on the CMAP Guide Guest Blog.
1.4.2.2 Notes
1.4.2.2.1 1 Note that not all variables are relevant to each study that may be reviewed or proposed.
1.4.2.2.2 2 Footnotes or other commentary and language will be added as needed to annotate a more detailed explanation of items. For example, the following comment has been added to Section 1.3.8.4.1.1 re exclusionary criteria.
1.4.2.2.2.1 Depending on the research design, such exclusionary criteria may be appropriate or not. For example, excluding subjects with a history of opiate use for pain in a study of cannabis use for pain could exclude the very individuals most likely to be helped by cannabis. On the other hand, it could be appropriate to exclude an opiate user as a subject in a study investigating whether there is a positive effect from cannabis on sleep apnea.
1.4.2.2.3 Similarly, the following note has been added about “new cultivar effect” and strain rotation in the section on “cannabis sample selection criteria” (Section, 1.3.8.5.4.1):
1.4.2.2.3.1 Cannabis is noteworthy for a “new cultivar effect,” whereby effectiveness may wear off until a new cultivar is used by the subject. If there is potential for “new cultivar effect” the study design may include a change or rotation of the cultivar.
1.4.2.3 Acknowledgements
1.4.2.3.1 This section acknowledges the CMAP founders and other initial contributors as well as the founding organizational sponsor.
1.4.2.3.1.1 * Robert Bornn, (CMAP Founder, writer, editor, publisher)
1.4.2.3.1.2 * Laura Worth, MSW (CMAP Founder, writer, editor, publisher)
1.4.2.3.1.3 * LifeSense Technologies, LLC – CMAP founding sponsor
1.4.2.3.1.4 * John Brown (CTO, Analytical 360, cannabis testing laboratory, certified by Washington state under I-502)
1.4.2.3.1.5 * Lex Pelger (writer, scientist, and Shulginist)
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