Translating the Clinical Reintegration

of Botanical Medicines:

CANNABIS BOTANY Jeffrey S. Block, M.D.

1. AN EVOLVING NATURAL EARTH SCIENCE………………………Pages 3-8

a) Biochemistry and Physiology: Common Ancestral Links Between Flora and Fauna

b) Contemporary Cannabis Presents a Challenge for Taxonomy

c) Genetics Brings Improved Accuracy to Botanical Science

2. A FIXED CHEMICAL RECEPTOR MEDICAL SCIENCE…………Pages 9-13

a) Botanical Alkaloid Discoveries Receive the Nobel Prize

b) Trichomes – Where the Plant’s Chemicals are Derived From

c) Studying Botanical Science is a Moving Target

3. AN APPLIED THERAPEUTIC SCIENCE.…………………………Pages 14-18

a) Why Would a Plant’s Chemicals Effect an Animal’s Receptors and Behavior?

b) How Do the Balanced Chemicals in Cannabis Restore “Homeostatic Physiology”?

c) Botany’s Basic Science Will Advance the Understanding Our Complex Physiology

References…………………………………………………………………… Page 19

Artwork Sources……………………………………………………………Page 20

About the Author………………………………………………………… Page 21

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Cannabis Botany: Translating the Clinical Reintegration of Botanical Medicine

Jeffrey S. Block, M.D.

SECTION 1: AN EVOLVING NATURAL EARTH SCIENCE

Biochemistry and Physiology: Common Ancestral Links Between Flora and Fauna

Evolutionary natural selection provides indirect evidence of mankind’s effective

use of botanical substances. Whether for nutrition or remedies, plant source

chemicals are essential to sustain life, and have been exploited by animals since the

beginning of time. Human life’s evolution along with plant life has revealed

common ancestral chemicals recognized to be essential to our health and survival.

One has only to look at the essential “life blood” molecules of hemoglobin next to

chlorophyll to appreciate that these remarkably similar chemistries connect an

ancient botanical past to the complexities of our evolved modern human

physiology.

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In ancient times, healers were depended on as horticultural botanists. If they did

not understand how to keep plants alive, healers would have lost their formulary

and most certainly have failed at their craft. From the earliest of primitive nomadic

tribes, to the advancing agricultural civilizations that followed, botany remains

central to mankind’s successful evolution.

Early civilization's "physician" healers included Imhotep (2667-2648 BC) in Egypt

and Hippocrates (460-370 BC) in Greece who understood and responsibly shared

the importance of plants to sustain health. These two historical figures are widely

regarded as The Fathers of Modern Medicine in that they recorded their botanical

findings to herald the beginning of the evidence-based healthcare science.

Unlike most plants that use several methods of distribution such as wind, insect

cross-pollination, or seed dispersal by animals; human agriculture is credited for

Cannabis’ worldwide transport from Asia began subsequent to the last ice age.

There is accumulating genomic evidence that native and natural traditional

landrace cannabis strains evolved its ancestral balance of synergistic

phytocannabinoids and essential oils that successfully co-evolved with humans to

find its way around the world.

Teleological discussions reason that if used by human beings for over 10,000 years,

these traditional Cannabis strains likely interplayed favorably with human genes to

meet the survival needs of an adaptive physiology. Considering mankind’s

successful survival along with cannabis since the last ice age, when intuitively

regarded as an ethnobotanical “experiment”, the evidence of human survival to

indicate a therapeutic tolerance supports evolution as the ultimate “knock-out”

design model. (*)

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Contemporary Cannabis Presents a Challenge for Taxonomy

As humans better understood living organisms, several systems to group plants and

animals were devised according to the available knowledge of that time. Mankind’s

current attempt to categorize plants into an acceptable taxonomy includes both

nomenclature and classification. The mid-18th century Linnaean hierarchal order in

use for naming organisms is based on eight taxa and includes: domain, kingdom,

phylum, class, order, family, genus, and species. Classification is the ordering of

items into groups based on similarities and/or differences; in biological

classification, species are one of the kinds of item to be classified. (1)

In botany, the starting point was in 1753; the year Carl Linnaeus first published

Species Plantarum using binomial nomenclature (genus; species). Renderings of

herbarium specimens and classical botanical drawings remain as the accepted

standard for plant identification because by convention they depict all parts of the

plant’s life cycle in a single image; including seeds, roots to stems, and leaves to

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flowers. The morphology and shape of a plant’s flowering parts was traditionally

used to determine many groupings.

Cannabis is also categorized as being dioecious because separate plants contain

either male or female reproductive organs, requiring cross-pollination to set seed.

One contributing reason why field grown male and female Cannabis plants often

have been referred to as “weeds” is because the male plant’s pollen is easily

windswept to nearby readily receptive female flowers to create seeds. Because the

greatest content of phytocannabinoid and terpene chemicals are found in un-

pollinated female flower bracts, the female plants are usually kept separate from

males to ensure that more energy contributes to plant chemical production rather

than seed production. Hence derives the Spanish word Sinsemilla meaning

“without seeds” to describe the female plant flower’s rich chemical content.

The two common Cannabis species used for medical purposes are referred to as

indica, and sativa. The existing nomenclature for the genus Cannabis is used to

legally distinguish its contrasting commercial uses.

Whereas few if any true pure landrace varietals actually still exist, today’s “medical

marijuana” as developed under Federal Prohibition more accurately refers to a

collective term representing man-made hybrids between traditional sativa and

recreationally popular indica species of the genus Cannabis.

Despite its cultivation as a source of food, fiber and medicine, and its global status

as the most frequently used illicit drug, the genus Cannabis currently has an

inconclusive taxonomic organization and evolutionary history. Drug types of

Cannabis (marijuana), which contain high amounts of the psychoactive

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cannabinoid THC, are used for medical purposes and as a recreational drug. Hemp

types are grown for the production of seed and fiber, and contain low amounts of

THC.

Hemp is a variety of Cannabis sativa plant species that is grown specifically for the

industrial uses of its derived products.(2) that can be refined into a variety of

commercial items including paper, textiles, clothing, biodegradable plastics, paint,

insulation, biofuel, food, and animal feed. (3)

Hemp plants are primarily male, without representing flowering buds at any stage

in their life cycle. Instead, centuries of selective breeding have resulted in relatively

low concentrations of THC, and tall, fast growing plants optimized for higher stalk

harvests.(5) Hemp is usually grown outdoors to maximize its size and yield and less

attention is paid to individual plants, while in contrast achieving maximum THC

levels in Cannabis sativa as a drug requires close attention to horticultural

conditions. Certain Cannabis strains known to contain more CBD than THC are

found within industrial hemp that have recently been of therapeutic interest for

treating neuro-movement disorders.

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Genetics Brings Improved Accuracy to Botanical Science

As the science of genetics vastly improves our understanding evolutionary nature,

the widely accepted genus and species binomial nomenclature designation has

increasingly been challenged, requiring frequent reconfigurations.

DNA-based research can offer botanists a better understanding of the relationships

between plant species. This knowledge will help them select plants that share

similar biochemical assays, thus guiding their screening and selection of plants for

potential medicinal use.

Marijuana strain names usually do not reflect a meaningful genetic identity. When

marijuana and hemp were differentiated at a genome-wide level, only a moderate

correlation between the genetic structure of marijuana strains and their reported

C. sativa and C. indica ancestry could be correlated. (5) Accurate data acquisition

from patient’s receiving a known cultivar’s chemical constituents will be essential

to responsibly advance therapeutic whole plant use, so reliable methods for

identifying whole plant genotypes are needed to safely advance translational

endocannabinoid research.

SECTION 2: A FIXED CHEMICAL RECEPTOR MEDICAL SCIENCE

Botanical Alkaloid Discoveries Receive the Nobel Prize

It had been known for thousands of years that plants had healing and curative

properties to restore physiological balances needed to sustain life. What was still

unknown were the chemical compounds responsible. That all changed in 1947

when post-World War Two science finally recognized one of the plant world’s most

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powerful weapons against human disease: Alkaloids. That year’s Nobel Prize in

Chemistry went to Sir Robert Robinson, whose citation speech including the

following passage: “They usually have striking, sometimes sensational

physiological effects. Among them are quinine, cocaine and atropine, all of which

have important medicinal qualities. Plants containing alkaloids have generally

drawn the attention of primitive peoples, and in the cases where they are met

within countries with ancient culture, the knowledge of their properties often

goes back to prehistoric age.” (6)

Botanical alkaloid sources derive ephedrine, curare, and aspirin, as well as addicting

substances such as cocaine, nicotine. Additional plant alkaloids also include

caffeine and chocolate that also bring habit-forming potential, but yet are common

to every-day life.

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Similar to how opium from the poppy flower eventually identified the endorphin

receptor system, so has the Cannabis plant’s essential botany revealed the

endocannabinoid receptor system it effects. These “hard-wired” receptors are

found not only in recently evolved human beings, but also in phylogenetically

primitive animals including invertebrates.

Although not an alkaloid, the chemical structure of Cannabis’ principal psychotropic

chemical, Δ9-tetrahydrocannabinol (THC) was elucidated in 1963, and its

biosynthetic pathways were determined soon after. However, the more significant

discovery occurred three decades later when the receptor system’s discovery

quickly led to finding its endogenous ligands discoveries that influence an

extraordinarily wide range of physiological activity.

Cannabis is a genus of flowering plants that includes multiple subspecies. Scientists

have identified over 400 chemical compounds produced by the cannabis plant.

More than 65 of these compounds are unique to the cannabis plant, and are

referred to as cannabinoids, or phytocannabinoids. Some examples of

phytocannabinoids include Δ9-tetrahydrocannabinol (THC), tetra-

hydrocannabivarin (THCV), cannabidiol (CBD), cannabichromene (CBC), and

cannabigerol (CBG).

THC and its analogues are derived from the cannabis plant, and can interact with

endogenous (endocannabinoid) receptors to affect the endocannabinoid system.

Phytocannabinoids have biological activity due to their receptor-based effects on

the endocannabinoid system. Additional pharmacological effects, such as anti-

inflammatory mechanisms may be non-receptor mediated. (7)

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Trichomes – Where the Plant’s Chemicals are Derived From

Trichomes are structures found on many plants that typically are involved as a

defense against desiccation. In the cannabis plant, capitate glandular trichomes

serve as chemical factories that process and store concentrations of biologically

active chemicals that include phytocannabinoids and essential oils. Under a

microscope they resemble crystalline mushrooms.

When collected from the plant flower’s leaf buds, the concentrate gathered is

commonly referred to as hashish.

The optimal harvest time for cannabis is regarded to be when a full complement of

trichomes are evidenced. This can be measured as a greater dry weight of the

sought after secondary metabolite chemicals, particularly the sole psychoactive

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component, THC. Under optimal conditions, from sowing seed through

germination and on to harvest generally requires between two and four months.

The past quarter century’s hybridized cultivars that have been systematically

selected under Cannabis Prohibition to feature the principal psychotropic chemical

constituent in cannabis. Selective hybridizing has concentrated the plant’s

psychotropic Δ9-tetrahydrocannabinol (THC) from what typically averaged 5% dry

weight in the 1970’s, to yields upward of 25%; a most remarkable horticultural feat

in search of a single secondary metabolite.

Alongside ethno-medical pointers from traditional medical plant lore, there are

modern hi-tech complements currently under development. Varied methods of

cultivation cause plants to differentially express their quantities of balanced

chemicals. This results from stressors that developing plants encounter reflecting

the conditions where and how they are grown. Quality improvement metrics

attempt to define cultivation and processing “best practice” parameters as needed

standards for plant production and chemical extraction techniques. The associated

agricultural and biochemical science industries consistently strive for

improvements in product safety and efficacy.

Studying Botanical Science is a Moving Target

Botany is both a natural earth and evolutionary science attempting to study

components of plant traits by investigating chemotypes or genotypes, however

these are relatively incomplete pictures of the plant as a successfully adapting life

form. Phenotype describes the overall composite expression of any organism’s

observable characteristics, including the biochemical and physiological properties

within that organism. (8) In both plants and animals, phenotypic variation is due to

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underlying heritable genetic variation, and is a fundamental prerequisite

determining evolution by natural selection. The success or failure of a plant or

animal as a whole contributes to the next generation, so natural selection affects

the genetic structure of a population indirectly via the contribution of phenotypes.

Without phenotypic variation, there would be no evolution by natural selection. (9)

SECTION 3: AN APPLIED THERAPEUTIC SCIENCE

Why Would a Plant’s Chemicals Effect an Animal’s Receptors and Behavior?

Modern advances in biochemistry and pharmacology have revealed many plant-

based molecule’s bioactive mechanisms of action to be channeled through

receptors serving as protein-molecules to receive chemical signals from outside

cells. Most biochemically active plant molecules used for medical purposes are

bitter tasting alkaloids that the plant has evolved as a defense against herbivores.

Although not an alkaloid, phytocannabinoids also appear to be anti-herbivorous.

Their bioactivity mimics aspects of endocannabinoid ligand functions, and are

effected through the largest single family of receptors known as Type 2, or G

protein-coupled receptors that include receptors for several hormones and slow

transmitters including dopamine (10)

How Do the Balanced Chemicals in Cannabis Restore “Homeostatic Physiology”?

In a clinical sense, the complex endocannabinoid receptor system’s principal health

function is simply to sustain an organism by constantly adjusting its physiology in

response to life’s stresses. From birth, CB1 receptor’s effect the ability to relax,

eat, sleep, and forget; while CB2 receptors appear to help protect from the

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consequence(s) of a disease essentially allowing them to become “chronic”. (11) End

of life issues often overwhelm the CB2 receptor’s far-reaching compensatory

effects to sustain life. Without the contribution of CB2 receptor function and an

effective immune system, life’s balanced physiology ceases, and death will ensue.

In addition to the best known phytocannabinoids including -9-

tetrahydrocannabidiol (THC), cannabidiol (CBD), and cannabinol (CBN), several

essential oil terpenes and flavonoids appear to be responsible for Cannabis strain’s

distinctive scents and character of effects but are far less well represented in

today’s limited formularies compared with a generation ago. Combinations of

plant derived chemicals are thought to interact with synergy referred to as an

“entourage effect”. (12) The same Afghani #1 widely used within most hybrids

contains a not only sedating, but particularly hypnotic terpene known as myrcene;

however, myrcene’s properties can be counter-balanced by combining or

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substituting it with one of several other essential oils. For example, the terpene

linalool is also found in the fragrance associated with lavender. This scent is used

in aromatherapy, in certain soaps, and is known to be calming, but is not

particularly hypnotic as myrcene appears to be. An awake, but calming effect is

often cited by users of strains of Cannabis that have synergistic levels of linalool, a

common terpene. Considering the wide array of cannabinoid and essential oil

combinations available to create any given patient’s safe and effective formulary,

a determination of optimally safe and balanced dose plant chemicals currently

presents significant therapeutic challenges for healthcare providers. Despite

cannabis’ widespread and frequent use, of additional concern is that little data has

been accumulated to understand its chemical’s effects on long-term down-

regulating the endocannabinoid system.

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The contemporary cannabis plant’s chemical constituents contrast markedly with

a traditional landrace form’s native and evolution balanced formulary. Associated

with the creation of this “modern plant”, includes the loss of several other

additional phytocannabinoids and essential oils; each known to have their own

unique bioactivity and potential clinical effects.

While under the influence of human agricultural horticulture in a Darwinian sense,

Cannabis species have been both naturally and un-naturally selected for

complements of its most desirable chemicals.

Contemporary western medicine regularly confronts the consequences of single

chemical “magic bullets” in treating disease. Failed therapeutic results from using

ala carte single plant molecules confound many physicians who underappreciate

why and how using a multi-combinatorial balanced therapeutic formulary can

provide improved, risk-assessed outcomes.

This offers an important advance for “modern medicine” in that combinations of

medicines, directly or derived from plant-based chemical have frequently held

therapeutic solutions for many of healthcare’s most notorious diseases.

A basic dictum of traditional Chinese medicine is to use combinations of several

herb-based chemicals to help control a disease, and is referred to as “surrounding

the dragon”; in Victorian times, a combination of up to four quinine alkaloids from

cinchona bark was determined to be more effective in treating the scourge of

malaria, likely by controlling more resistant parasites; and when HIV and AIDS

treatments began in the mid-1980’s, a combined “cocktail” of different drugs were

similarly used to help control the disease.

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Botany’s Basic Science Will Advance the Understanding Our Complex Physiology

Because nearly all Cannabis cultivars available today are man-made hybrids,

agricultural science and genomics have started to reveal common ancestral genes

in a search for the heirloom plant’s ancestral strains that existed in the past.

21st-century botanical genomics can select for plants having beneficial traits such

as disease resistance, higher yields, and unique balances of therapeutic chemicals.

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A March, 2016 acknowledgement concerning the clinical importance to investigate

representative mixtures of balanced phytocannabinoid and essential oil chemicals

was recently shared by the Commissioner of the United States Food and Drug

Administration (FDA) at an open access collaborative summit sponsored by the

National Institutes of Health.(13) The FDA has been evaluating Sativex that

represents a combination of phytocannabinoid chemicals for adult patients

suffering from debilitating muscle spasms associated with multiple sclerosis. The

value of multiple pathway approaches to understanding disease is part of a new

goal to find cures for cancer that complement immune system function. A multi-

factorial interaction approach to healthcare has been increasingly appreciated by

the United States government, and endocannabinoid science’s contributions to

understand homeostatic physiology’s effect on the immune system’s optimal

function appear central to this task.

“Stemming” from ten thousand years of a most common plant’s cultural usage,

The National Institute of Health now envisions that “modulating the

endocannabinoid system may have therapeutic potential in almost all diseases

affecting humans.” (14)

This most remarkable statement reconnects botany to the future for healthcare.

/jsbmd

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REFERENCES (*) Re: Author’s exception: Teleological paragraph’s inclusion within cannabis (ethno)botany education. “In modern science, explanations that rely on teleology are often, but not always, avoided, either because they are unnecessary or because whether they are true or false is thought to be beyond the ability of human perception and understanding to judge.” Ransom Johnson, Monte (2008), Aristotle on Teleology, Oxford University Press pages 23-24.

(1) Manktelow, M. (2010) History of Taxonomy - Lecture from Dept. of Systematic Biology, Uppsala University.

(2) Swanson, TE (2015), "Controlled Substances Chaos: The Department of Justice's New Policy Position on Marijuana and What It Means for Industrial Hemp Farming in North Dakota" (PDF), North Dakota Law Review, 90 (3): 613

(3) "Erowid Cannabis Vault : Culture #2". erowid.org. Retrieved 2008-06-20.

(4) http://www.leafscience.com/2014/09/16/5-differences-hemp-marijuana/

(5) The Genetic Structure of Marijuana and Hemp Jason Sawler, Jake M. Stout, Kyle M. Gardner, Darryl Hudson, John Vidmar, Laura Butler, Jonathan E. Page, Sean Myles PLoS One. 2015; 10(8): e0133292. Published online 2015 August 26. doi: 10.1371/journal.pone.0133292

(6) http://www.thekingdomofplants.com/2014/08/26/bbc-plants-podcast-roots-riches/ Plants - Roots to Riches (pg. 200) Willis; Fry – (Kew Gardens) Botanical Medicine – August, 2014

(7) Pacher et al. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacological Reviews 2006; 58: 389-462.

(8) https://en.wikipedia.org/wiki/Phenotype

(9) Lewontin, R. C. (November 1970). "The Units of Selection" (PDF). Annual Review of Ecology and Systematics. Palo Alto, CA: Annual Reviews. 1: 1–18. doi:10.1146/annurev.es.01.110170.000245. ISSN 1545-2069. JSTOR 2096764.

(10) https://en.wikipedia.org/wiki/Receptor_(biochemistry)

(11) Vincenzo Di Marzo, et al. Trends Neuroscience (1998) 21, 521-528

(12) Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects Br J Pharmacol. 2011 Aug; 163(7): 1344–1364. doi: 10.1111/j.1476-5381.2011.01238.x

(13)https://www.youtube.com/watch?v=nhl_3sPHIRw&index=12&list=PLE4ZNGaomJBnFoW82EjtVAtRimC84B3Bm Robert M. Califf, M.D., Commissioner, FDA (Closing Remarks 6:15-6:50 min.)

(14) Modulating the endocannabinoid system in human health and disease – successes and failures

FEBS J. 2013 May; 280(9): 1918–1943. Published online 2013 Apr 22.

doi: 10.1111/febs.12260 Pal Pacher and George KunosLaboratory of Physiologic Studies, NIAAA, NIH, Bethesda, MD, USA

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ARTWORK SOURCES

1. http://www.nadyapeche.com/the-green-blood/

2. Cannabis – Evolution and Ethnobotany by Robert C. Clark and Mark D. Merlin (2013) Figure 38 (modified)

3. http://redeyesonline.net/indica-vs-sativa/

4. Compilation by Jeffrey S. Block, M.D. (The classical botanical prints extracted here can be accessed on multiple online sites.)

5. Photo and middle close-up detail by Jeffrey S. Block, M.D. Top right electron microscopy insert: http://9gag.com/gag/aX9ABEv/thc-trichomes-under-an-electron-microscope

6. Therapeutic patient care clinical model of endocannabinoid receptor system function for. Jeffrey S. Block, MD

7. FROM Slide by Jeffrey S. Block, MD; Fig. 12 (modified) Cannabis – Evolution and Ethnobotany by Clark and Merlin (2013)

8. Molecular Phylotyping of Cannabis - Ryan Lynch, PhD et al. Genomic and Chemical Diversity of Cannabis New Phytologist in review or pre-print is up on BioRxiv (Medicinal Genomics CannMed 2016). Slide 14 (modified)

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Jeffrey S. Block, M.D. DocBlock@NurturingNature.com DocBlock@Miami.edu is a nationally respected authority in both the health-care and natural earth sciences concerning botanical medicine education and research; and the founding principal partner of Nurturing Nature® Group Consultants, a professional independent consultancy providing client organizations with advanced scientific guidance. This industry-wide consultancy provides insight by translating an evolving new science’s evidence-based objective data. These essential analyses benefit his client’s ultimate success by providing knowledge of critical competitive advantages needed to reach performance goals.

He achieved his bachelor’s degree from Emory University (1978) majoring in analytical chemistry with a minor in psychology and received his Medical Doctorate from the University of Miami (1982). Block is an American Board-Certified Anesthesiologist who is additionally Fellowship trained in Pain Management & Addiction Medicine. In 2018, Medical book publisher CRC Press resourced Dr. Block’s expertise authoring their book’s content concerning the endocannabinoid receptor system’s potential for therapeutic pain management. “DocBlock” has served as President of UM’s Miller School of Medicine’s Medical Alumni Association and has shared his diverse expertise as a popular voluntary medical Professor and subject lecturer.

This unique combination of science and education backgrounds additionally include being an internationally awarded horticulturist and water quality expert as CEO of Block Botanical Gardens in Miami, Florida; a leading Institutional Member of the American Public Gardens Association (APGA). In this capacity, Dr. Block also serves the Florida Department of Agriculture Extension Office’s programming as a highly regarded Certified Master Gardener and course educator for the University of Florida Institute of Food and Agricultural Sciences.

Block was chosen as the Florida Medical Association (FMA) “Designated Expert on Botanical Medicines” and was appointed to structure the framework and author the introductory chapter for physician education as mandated by Florida’s Compassionate Medical Cannabis Act of 2014. He subsequently was selected by Florida’s Surgeon General to serve as the only physician appointed to Florida’s Department of Health Negotiated Rule-Making Committee that determined the existing rules regarding Florida’s first botanical medicine legislation concerning endocannabinoid receptor responses to non-psychoactive cannabidiol cultivars known as “Charlotte’s Web” strains. As a highly qualified and trusted national educator on cannabinoid medicine, in 2017 Professor Block was chosen to lecture physicians at the University of Miami’s Miller School of Medicine “Grand Rounds” case presentations, at that institution’s Annual Integrative Medicine Conference; at Nova Southeastern School of Pharmacy; Skype lectures for the University of Colorado; for Baptist Health of South Florida Primary Care Symposium; for the Miami-Dade Medical Association; and as the Keynote speaker for Colorado’s biannual Marijuana for Medical Professionals conference & California’s competitive annual Emerald Cup.